PT1954699E - Pyrido-, pyrazo- and pyrimidopyrimidine derivatives as mtor inhibitors - Google Patents

Description

DESCRIPTION

" PYRID-, PYRAZO- AND PYRIMIDOPYRIMIDINE DERIVATIVES AS MTOR INHIBITORS " The present invention relates to compounds, pyrido-, pyrazo- and pyrimido-pyrimidine derivatives, which act as inhibitors of mTOR.

Background Activation by the growth / mitogenic factor of the phosphatidylinositol 3 (PI3K) / AKT kinase signaling pathway ultimately leads to the key cell cycle regulator and growth control mTOR, the mammalian target of rapamycin (alternatively referred to as such as FRAP (FKBP12-associated protein and rapamycin), RAFT1 (target 1 of Rapamycin and FKBP12), RAPT1 (target 1 of rapamycin) - all derived from interaction with the FK-506 binding protein, FKBP12 and SEP (sirolimus effector protein )). MTOR is a mammalian serine / threonine kinase of approximately 289 kDa in size and a member of evolutionary conserved eukaryotic TOR kinases (ref. 1-4). The mTOR protein is a member of the PI3 kinase analogous kinase (PIKK) family of proteins because of its C-terminal (catalytic domain) homology to the PI3 kinase and the other members of the family, e.g. DNA-PKc (DNA-dependent protein kinase), ATM (mutated ataxia-telangiectasia). In addition to a catalytic domain at the C-terminal end, mTOR contains a FKBP12 / rapamycin (FRB) complex binding domain. At the 1 N-terminus are up to 20 HEAT motifs (Huntingtina, EF3, alpha regulatory subunit of PP2A and TOR) while more C-terminal is a FAT domain (FRAP-ATM-TRRAP) and at the C-terminal end of the protein an additional FAT domain (FAT-C) is found (ref 5,6). TOR has been identified as a central regulator of growth (size) and cell proliferation, which is governed in part by the initiation of translation. TOR-dependent phosphorylation of S6 kinase (S6K1) allows the translation of ribosomal proteins involved in cell cycle progression (ref 7-9). Cap dependent translation is regulated by the phosphorylation of the binding protein 1 (4E-BP (PHAS-1)) to the eukaryotic translation start factor 4E (eIF4E). This modification prevents PHAS-1 from binding to eIF4E, thereby allowing the formation of an active eIF4F translation complex (reviewed in refs. 10, 11, 12). Activation of these signaling elements is dependent on insulin, other growth factors and nutrients suggesting a portal role for mTOR in controlling cell cycle progression only under favorable environmental conditions. The PI3K / AKT signaling cascade is located upstream of mTOR and has been shown to be dysregulated in certain cancers and results in the independent activation of growth factor, for example in PTEN-deficient cells. MTOR is located on the axis of control for this pathway and inhibitors of this kinase (eg, sirolimus (Rapamycin or Rapamune ™) and everolimus (RAD001 or Certican ™) are already approved for immunosuppression and drug endoprostheses (reviewed in ref 13, 14) and are now receiving particular attention as novel agents for the treatment of cancer. Growth of tumor cells arises from the deregulation of normal mechanisms of growth control such as loss of tumor suppressor function (s). One such tumor suppressor is the homolog of phosphatase and deleted tensin of chromosome ten (PTEN). This gene, also known to be mutated in several advanced cancers (MMAC), has been shown to play a significant role in cell cycle arrest and is the most highly mutated tumor suppressor after p53. Up to 30% of glioblastomas and cancers of the endometrium and prostate have somatic mutations or deletions of this locus (ref 15, 16). PI3K converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3), while PTEN is responsible for removing 3 'phosphate from PIP3 producing PIP2. PI3-K and PTEN act to maintain an appropriate level of PIP3, which thereby recruits and activates AKT (also known as PKB) and downstream signaling cascade which is then initiated. In the absence of PTEN there is an inappropriate regulation of this cascade, AKT becomes effectively constitutively activated and cell growth is deregulated. An alternative mechanism for the deregulation of this cellular signaling process is the recent identification of a mutant form of the PI3K isoform, pllOalpha (ref 17). It is believed that the increased apparent activity of this mutant results in a greater production of PIP3, presumably greater than that which the PTEN function can neutralize. Further signaling from PI3K thus results in increased signaling for mTOR and, therefore, for activators downstream thereof.

In addition to the evidence linking mTOR to cell cycle regulation (from G1 to S phase) and inhibition of mTOR results in inhibition of these regulatory events, negative regulation of mTOR activity has been shown to result in inhibition of cell growth ( Revised in refs. 7, 18, 19). The known inhibitor of mTOR, rapamycin, strongly inhibits the proliferation or growth of cells derived from a range of tissue types, such as smooth muscle, T cells, as well as cells derived from a varied range of tumor types including rhabdomyosarcoma, neuroblastoma , glioblastoma and medulloblastoma, small cell lung cancer, osteosarcoma, pancreatic carcinoma, and breast and prostate carcinoma (reviewed in ref 20). Rapamycin has been approved and is in clinical use as an immunosuppressant, with its prevention of organ rejection successful and with fewer side effects than previous therapies (ref 20,21). Inhibition of mTOR by rapamycin and its analogs (RAD001, CCI-779) is brought about by the prior interaction of the drug with the FK506 binding protein, FKBP12.

Subsequently, the FKBP12 / rapamycin complex then binds to the mTOR FRB domain and inhibits downstream mTOR signaling.

The potent but non-specific inhibitors of PI3K, LY294002 and vortmanin have also been shown to inhibit mTOR kinase function but to reach the catalytic domain of the protein (ref.21). In addition to the inhibition of mTOR function by small molecules directed to the kinase domain, it has been shown that mTOR with knockout void can not transmit the upstream activation signals to effectors downstream of mTOR, PHAS-1 or p70S6 kinase (ref 22). It has also been shown that not all mTOR functions are sensitive to rapamycin and this may be related to the observation that rapamycin alters the substrate profile of mTOR rather than inhibiting its activity per se (ref 23). Analysis of the interactions of mTOR with other cellular factors revealed that, in addition to the mTOR-Raptor complex, there is also an mTOR-Rictor complex representing an insensitive activity to mTOR (B) rapamycin (Sarbassov et al., Current Biology, 2004, 14, 1296-1302). This activity is probably responsible for the discrepancy between mTOR and kinase mutation and

signaling of mTOR by rapamycin and its derivatives. The discrepancy also identifies the possibility of a therapeutic advantage by directly inhibiting the catalytic activity of mTOR. It has been suggested that a catalytic inhibitor of mTOR may be a more effective antagonist of the proliferation and survival of cancer cells and that rapamycin may be more useful in combination with agents that can compensate for this insufficiency to completely break down the pathway signaling (Choo and Blenis, Cancer Cell, 2006, 9, 77-79; Hay, Cancer Cell, 2005, 8, 179-183). Therefore, it is proposed that a mTOR inhibitor directed to the kinase domain may be a more effective inhibitor of mTOR.

In addition to the ability of rapamycin to induce growth inhibition (cytostasis) on its own, it has been shown that rapamycin and its derivatives potentiate the cytotoxicity of a number of chemotherapies including cisplatin, camptothecin and doxorubicin (reviewed in ref 20). Potentiation of the cell death induced by ionizing radiation after inhibition of mTOR (ref 24) was also observed. Experimental and clinical trials have shown that rapamycin analogs are showing evidence of efficacy in the treatment of cancer alone or in combination with other therapies (see ref. 10, 18, 20). These findings suggest that the pharmacological inhibitors of mTOR kinase should be of therapeutic utility for the treatment of various forms of cancer comprising solid tumors, such as carcinomas and sarcomas, and leukemias and lymphoid malignancies. 5

In particular, mTOR kinase inhibitors should be of therapeutic utility for the treatment of, for example, breast, colon and rectal cancer, lung (including small cell lung cancer, non-small cell lung cancer, and bronchoalveolar cancer ) and prostate, and cancer of the biliary tract, bone, liver, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testis, thyroid, uterus, cervix and vulva, and leukemias including ALL and CML), multiple myeloma and lymphomas.

In particular, renal cell carcinoma was identified as being sensitive to the CCI-779 rapamycin derivative resulting from the loss of VHL expression (Thomas et al., Nature Medicine, 2006, 12, 122-127). Promotorocytic leukemia (PML) tumor suppressor tumors have also been shown to be sensitive to inhibition of mTOR by rapamycin as a consequence of disruption of regulation of the mTOR signaling pathway (Bemadi, Nature, 2006, 442, 779-785 ) and the use of an mTOR kinase inhibitor in such diseases should be of therapeutic utility. These latter examples, in addition to those of PTEN deficiency or PI3K mutation, indicate that a targeted approach to the use of mTOR inhibitors may prove particularly effective because of an underlying genetic profile but are not considered to be unique targets.

Recent studies have revealed a role for mTOR kinase in other diseases (Easton & Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564). Rapamycin has been shown to be a potent immunosuppressant inhibiting T-cell proliferation, B-cells and antigen-induced antibody production (Sehgal, Transplantation Proceedings, 2003, 35, 68S-14S) and, thus, the kinase inhibitors of mTOR may also be useful immunosuppressants. Inhibition of mTOR kinase activity may also be useful in preventing restenosis, i.e. control of the unwanted proliferation of normal cells in the vasculature in response to the introduction of endoprostheses in the treatment of vasculature disease (Morice et al., New England Journal of Medicine, 2002, 346, 1773-1780). In addition, the Rapamycin analogue, everolimus, may reduce the severity and incidence of cardiac allograft vasculopathy (Eisen et al., New England Journal of Medicine, 2003, 349, 847-858). High activity of mTOR kinase has been associated with cardiac hypertrophy, which is of clinical importance as a very important risk factor for heart failure and is a consequence of increased cardiomyocyte cell size (Tee & Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). Thus, mTOR kinase inhibitors are expected to be useful in preventing and treating a wide variety of diseases other than cancer. The vast majority of the pharmacology of mTOR to date has focused on the inhibition of mTOR through rapamycin or its analogs. However, as noted above, the only non-rapamycin agents which have been described to inhibit the activity of mTOR through a mechanism directed to the kinase domain are the small molecule LY294002 and the natural product vortmanin (ref.21). EP0185259 (Dr. Karl Thomae GMBH) discloses certain pteridines having useful pharmacological properties, more particularly with antithrombotic and inhibiting effects of metastases and antitumor inhibitory activity. 7

Summary of the Invention The present inventors have identified compounds that are competitive inhibitors of mTOR ATP and, consequently, are not analogous to rapamycin in its mechanism of action.

Accordingly, the first aspect of the present invention provides a compound of formula I:

wherein: X8 is N, and X5 and X6 are CH; R7 is a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 aryloxy, C5-2 aryl, amino, acylamido, acyloxy, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, heteroaryl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkenyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 aryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino);

R 3 and R 4 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C 1-7 alkyl, C 2-12 alkenyl C7-7 cycloalkenyl, C3-7 cycloalkenyl, C3-20 cycloalkenyl, C5-20 aryl, C5-20 aryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups. optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-22 heterocyclyl, C5_20 aryl, C5-20 heteroaryl, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R 2 is selected from NR 5 R 6, a C 5-20 heteroaryl optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy and thiol, or C 1-6 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl C3-20 heterocyclyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, nitro, cyano, carboxy, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-10 heterocyclyl, C 5-10 aryl, C 2-10 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and a C20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, 7 / C2-7 alkynyl, C3-7 cycloalkyl C3-20 cycloalkenyl, C3-20 cycloalkenyl, C3-20 aryl, C5-20 aryl, heteroaryl, C3-6 heterocyclyl, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups halo, hydroxy, nitro, cyano, carboxyl, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-12 heterocyclyl, C 5-12 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy , thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), wherein R 5 and R 6 are independently selected from H, a C 1-7 alkyl group, a C 5-20 heteroaryl group and a C 5-20 aryl group or R 5 and R 6 together with nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms wherein each C 1-7 alkyl, C 5-12 heteroaryl, C 1-10 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxy nitro, cyano, carboxy and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-20 aryl, C 5-20 heteroaryl, acyl ester, amido, amino, acylamido , each of which is optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C7-7 cycloalkenyl, C3-2cycloalkenylC3-2cn arylC5-2cn heteroarylC5_20 / · ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfoxide, sulfonyl, thioamido and sulfonamino groups), or a pharmaceutically acceptable salt thereof and wherein " C5-20 aryl " as used herein refers to a monovalent unit obtained by removing a hydrogen atom from an aromatic endocyclic atom of a C5-20 aromatic compound, said compound having a , or two or more rings (e.g. fused), and having from 5 to 20 endocyclic atoms, and wherein at least one of said ring or rings is an aromatic ring and wherein the endocyclic atoms may include one or more heteroatoms, including but not limited to oxygen , nitrogen and sulfur; " alkyl " as used herein refers to a monovalent unit obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise noted), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated); " alkenyl " as used herein refers to an alkyl group having one or more carbon-carbon double bonds; " alkynyl " as used herein refers to an alkyl group having one or more carbon-carbon triple bonds; " cycloalkyl " as used herein refers to an alkyl group which is also a cycloalkyl group; i.e. a monovalent unit obtained by removing a hydrogen atom from an alicyclic ringocyclic atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated), a having from 3 to 20 carbon atoms (unless otherwise indicated), including from 3 to 20 endocyclic atoms; " ether " as used herein refers to a group -OR, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-20 aryl group; " acyl " as used herein refers to a group -C (= O) R, wherein R is H, a C1-6 alkyl group, a C3_20 heterocyclyl group or a C5-20 aryl group; " ester " as used herein refers to a -C (= O) O group, wherein R 1 is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-20 aryl group; " starch " as used herein refers to a -C (= O) NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, C 1-7 alkyl, C 3-12 heterocyclyl group or C 5-20 aryl group, or R 1 and R 2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms; " amino " as used herein refers to a group -NR 1 R 2, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group, or R 1 and R 2 taken in together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms; &Quot; acylamido " as used herein refers to a group -NR 1 C (= O) R 2, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-20 aryl group; C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group or R1 and R2 may together with the atoms to which they are attached form a succinimidyl, maleimidyl and phthalimidyl group; " ureido " as used herein refers to a group -N (R1) CONR2 R3, wherein R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R2 and R3, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms, and R1 is hydrogen, a C1-7 alkyl group, a C3-210 heterocyclyl group or a C5-20 aryl group; " acyloxy " as used herein refers to a -OC (= O) R group, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-20 aryl group; " thioether " as used herein refers to a -SR group, wherein R 1 is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group; " sulphoxide " as used herein refers to a group -S (= O) R, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-10 aryl group; " sulfonyl " as used herein refers to a group -S (= O) 2 R, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-20 aryl group; 13 " thioamido " as used herein refers to a -C (= S) NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group , or R 1 and R 2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms; " sulfonamino " as used herein refers to a group -NR 1 S (= O) 2 R, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group, and R is a C1-7 alkyl, a C3-20 heterocyclyl group or a C2-20 aryl group; and with the proviso that when R 2 is unsubstituted morpholino, R 3 and R 4 together with the nitrogen atom to which they are attached form an unsubstituted morpholino, R 7 is not unsubstituted phenyl, and when R 2 is unsubstituted piperidinyl, R 3 and R 4 together with the nitrogen atom to which they are attached form an unsubstituted piperidinyl, R 7 is not unsubstituted phenyl.

According to a second aspect of the present invention there is provided a compound of formula I (A):

wherein: X8 is N, and X5 and X6 are CH;

R3 and R4 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or haloC1-7 C2-7 alkenyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3_2cycloalkenyl, C5-2 aralkyl, C5-2 heteroaryl, ether, amide, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C2-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R2 is selected from NRn5Rn6, a C5_20 heteroaryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-6 cycloalkenyl, 7, C3-20 heterocyclyl / C5-20 aryl, heteroaryl C5-20 fatty ether, acyl ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxy, nitro cyano, carboxy, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkenyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-20 heterocyclyl, C 5-20 heteroaryl ether, acyl ester, amido amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, cyclo aryl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino groups (each optionally substituted with one or more groups selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy, , hydroxy, nitro, cyano, carboxyl, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-10 heterocyclyl, C 20-20 aryl, C 5-10 heteroaryl, ether, acyl, ester, amido, amino, acylamido , ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), wherein R N5 and R N6 are independently selected from H, a C1-7 alkyl group, a C5-20 heteroaryl group and a C5-20 aryl group or RN5 and RN6 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms wherein each C 1-7 alkyl, C 20 heteroaryl, C 5-20 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, h heteroaryl, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3_2cycloalkyl, C5_2aryl, C5-2 heteroaryl, ether, acyl ester, amido, amino, acylamido, (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl, C2-7cycloalkyl, C2-7cycloalkyl, C 3-7 cycloalkenyl, C 3-8 heterocyclylC 5-20 arylC 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R03 is selected from hydrogen or a C1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3 heterocyclyl Acyloxy, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxyl, thiol, C 1-2 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 2-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido , acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); and

R11 is selected from C (= O) Rc2, C (= S) Rc3, SO2 R3, a C5-2 heteroaryl optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, 7, C2-7 alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, C3-6cycloalkenyl, C5_20aryl, C5_20heteroaryl, C5_2o, ether, acyl, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 alkynyl, C3-7 cycloalkenyl, C3_7 cycloalkenyl, C5_2cycloaryl, C5-2 heteroaryl ether, acyl ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkenyl, C3-7 cycloalkenyl, C3-2cycloalkenylC5-2 aryl, C5-210heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups. optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-2 cycloalkenyl, C3-7 cycloalkenyl, C5-2 cycloalkenyl, heteroaryl, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups), or a C1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-4 alkyl Aryl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino groups (C 1 -C 7 -alkyl, C 2 -C 7 -alkenyl, C 1 -C 4 -alkyl, W optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 aryloxy, C5-20 aryl heteroaryl, C5-20 ether, acyl ester, amido , amino, acylamido, ureido, acyloxy, thioether, sulfoxido, sulfonyl, thioamido and sulfonamino) wherein R 1 and R 2 are selected from H, a C 20-20 aryl group, a C 5-7 heteroaryl group, a C 1-7 alkyl or NR 11 R 11 group, wherein R 11 and R11 are independently selected from H, a C1-4 alkyl group, a C20-20 aryl heteroaryl group or a R11 and R11 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms , wherein each C 1-7 alkyl, C 5-20 heteroaryl, C 5-20 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-12 heterocyclyl, C 5-12 heteroaryl, C 5-20 heteroaryl, acyl ester, amido, amino, acylamido, ureido, acyloxy thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); and R 3 is selected from H, a C 5-20 aryl group, a C 5-10 heteroaryl group or a C 1-7 alkyl group wherein each C 1-7 alkyl, C 5-10 heteroaryl or C 5-10 aryl is optionally substituted with one or more groups selected from halo, hydroxy, nitro , cyano, carboxy and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkenyl, C 3-7 cycloalkenyl, C 3-10 heterocyclyl, C 5-20 aryl, C 5-20 heteroaryl, ether, acyl ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C2-20 aryl, C2-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfoxide, sulfonyl, thioamido and sulfonamino), or a pharmaceutically acceptable salt thereof, and where " C5-20 aryl " as here used refers to a monovalent unit obtained by removing a hydrogen atom from an aromatic endocyclic atom of a C 5-7 aromatic compound having said compound having one ring, or two or more rings (e.g. fused), and having from 5 to 20 endocyclic atoms, and wherein at least one of said ring or rings is an aromatic ring and wherein the endocyclic atoms may include one or more heteroatoms, including but not limited to oxygen , nitrogen and sulfur; " alkyl " as used herein refers to a monovalent unit obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise noted), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated); " alkenyl " as used herein refers to an alkyl group having one or more carbon-carbon double bonds; " alkynyl " as used herein refers to an alkyl group having one or more carbon-carbon triple bonds; " cycloalkyl " as used herein refers to an alkyl group which is also a cycloalkyl group; i.e. a monovalent unit obtained by removing a hydrogen atom from an alicyclic endocyclic atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated), which unit has from 3 to 20 carbon atoms (unless otherwise indicated), including from 3 to 20 ring atoms; " ether " as used herein refers to a -OR group, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-10 aryl group; " acyl " as used herein refers to a -C (= O) R group, in which R 1 is H, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-10 aryl group; " ester " as used herein refers to a -C (= O) O group, wherein R 1 is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group; " starch " as used herein refers to a -C (= O) NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, a C 1-6 alkyl group, a C 3-12 heterocyclyl group or a C 5-20 aryl group, or R 1 and R 2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring having from 4 to 8 ring atoms; " amino " as used herein refers to a group -NR 1 R 2, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group or R 1 and R 2, taken together with the nitrogen to which they are attached form a heterocyclic ring having from 4 to 8 ring atoms; " acylamido " as used herein refers to a group -NR 2 C (= O) R 2, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group, R 2 is a C1-6 alkyl group, a C3-20 heterocyclyl group or a C20-20 aryl group or R1 and R2 may, together with the atoms to which they are attached, form a succinimidyl, maleimidyl and phthalimidyl group; " ureido " as used herein refers to a group -N (R1) CONR2 R3, wherein R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, or R2 and R 3 taken together with the nitrogen atom to which they are attached form a heterocyclic ring having from 4 to 8 carbon atoms, and R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-10 aryl group; " acyloxy " as used herein refers to a -OC (= O) R group, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-20 aryl group; " thioether " as used herein refers to a -SR group, wherein R 1 is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-20 aryl group; " sulphoxide " as used herein refers to a group -S (= O) R, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-10 aryl group; " sulfonyl " as used herein refers to a group -S (= O) 2 R, wherein R 1 is a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-10 aryl group; " thioamido " as used herein refers to a group -C (= S) NR 1 R 2, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-10 aryl group, or R 1 and R 2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring having from 4 to 8 ring atoms; " sulfonamino " as used herein refers to a group -NR 1 S (= O) 2 R, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 20-20 aryl group and R is C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group

According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula 1 or 1 (A), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

According to a further aspect of the present invention there is provided the formula 1 or 1 (A), or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body.

According to a further aspect of the present invention there is provided the use of a compound of formula 1 or 1 (A), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a disease enhanced by inhibition of mTOR.

Other aspects of the invention provide the use of a compound of formula 1 or 1 (A), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of: cancer, immunosuppression, immunological tolerance, autoimmune disease, inflammation, bone loss, bowel disorders, liver fibrosis, hepatic necrosis, rheumatoid arthritis, restenosis, cardiac allograft vasculopathy, psoriasis, beta-thalassemia, 23 and ocular conditions such as dry eye. Inhibitors of mTOR may also be effective as antifungal agents. The inventors have determined that the compounds defined in the present invention, or a pharmaceutically acceptable salt thereof, are effective anticancer agents, the property of which is believed to result from their mTOR inhibitory properties. Accordingly, the compounds of the present invention are expected to be useful in the treatment of diseases or conditions mediated only or in part by mTOR, i. and. the compounds may be used to produce an mTOR inhibitory effect in a warm-blooded animal in need of such treatment.

Thus, the compounds of the present invention provide a method of treating cancer characterized by the inhibition of mTOR, i. and. the compounds may be used to produce an anticancer effect mediated only or in part by the inhibition of mTOR.

Such a compound of the invention is expected to possess a wide range of anticancer properties, since activation mutations in mTOR have been observed in many human cancers, including but not limited to, melanoma, papillary thyroid tumors, cholangiocarcinomas, colon cancers , ovary and lung. Thus it is expected that a compound of the invention will possess anticancer activity against these cancers. Furthermore, it is expected that a compound of the present invention will possess activity against a range of leukemias, lymphoid malignancies and solid tumors such as carcinomas and sarcomas in tissues such as the liver, kidney, bladder, prostate, breast and pancreas. In particular, the compounds of the invention are expected to advantageously slow the growth of primary and recurrent solid tumors, for example, of the skin, colon, thyroid, lungs and ovaries. More particularly, such compounds of the invention, or a pharmaceutically acceptable salt thereof, are expected to inhibit the growth of those primary and recurrent solid tumors that are associated with mTOR, especially those tumors that are significantly dependent on mTOR for their growth and dissemination, including , for example certain tumors of the skin, colon, thyroid, lungs and ovaries. In particular, the compounds of the present invention are useful in the treatment of melanomas.

Thus, according to this aspect of the invention there is provided a compound of the formula I or I (A), or a pharmaceutically acceptable salt thereof, as defined herein to be used as a medicament.

According to a further aspect of the invention there is provided the use of a compound of the formula I or I (A), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the production of an mTOR inhibitory effect in a warm-blooded animal such as man.

According to this aspect of the invention there is provided the use of a compound of the formula I or I (A), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the production of an anticancer effect in an animal of warm blood like man.

According to a further feature of the invention there is provided the use of a compound of the formula I or I (A), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cholangiocarcinomas, melanoma , papillary thyroid tumors, colon cancer, ovarian cancer, lung cancer, leukemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lungs and ovaries.

In another aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula I or I (A), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically acceptable diluent or carrier for use in the production of an inhibitory effect of mTOR on a warm-blooded animal such as man.

In another aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula I or I (A), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically acceptable diluent or carrier for use in the production of an anticancer effect in a warm-blooded animal such as man.

In another aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula I or I (A), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of melanoma, papillary thyroid tumors, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as man.

A further aspect of the invention provides the use of a compound of formula 1 or 1 (A), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use as an adjunct in the therapy of cancer or to potentiate tumor cells for treatment with ionizing radiation or chemotherapeutic agents.

The compounds of the invention may be used for the treatment of disease improved by the inhibition of mTOR, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula 1 or 1 (A), or a pharmaceutically acceptable salt thereof , preferably in the form of a pharmaceutical composition and for the treatment of cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound as defined in the first or second aspect in association, form of a pharmaceutical composition, simultaneously or sequentially with ionizing radiation or chemotherapeutic agents.

Definitions The term " aromatic ring " is used herein in the conventional sense to refer to a cyclic aromatic structure, i.e., a structure having delocalized π electron orbitals. 27

A nitrogen-containing heterocyclic ring having from 3 to 8 ring atoms, as used herein, refers to a 3- to 8-membered heterocyclic ring containing at least one atom of endocyclic nitrogen. The term " together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms " as used herein refers to a 3- to 8-membered heterocyclic ring containing at least one ring nitrogen atom . Examples of such groups include, but are not limited to, thi aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (eg, 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), piperidine (C6), dihydropyridine (Ce), tetrahydropyridine (Ce), azepine (C7); N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine (C6); N1O1: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (Ce), tetrahydrooxazine (Ce), dihydrooxazine (Ce), oxazine (Ce); N 1 S 1: thiazoline (C 5), thiazolidine (C 5), thiomorpholine (Ce); N20i: oxadiazine (Ce); N (O) Si: oxathiazine (Ce). 28

Alkyl: The term " alkyl " as used herein refers to a monovalent unit obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise noted ), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated). Thus, the term " alkyl " includes the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, etc. subclasses discussed below.

In the context of alkyl groups, the suffixes (e.g., C1-4, C1-7, C12-2), C2-7, C3-7, etc.) denote the number of carbon atoms, or range of carbon numbers. For example, the term " C 1-4 alkyl " as used herein refers to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of alkyl groups include C 1-4 alkyl ("lower alkyl,"), C 1-7 alkyl and C 1-2 alkyl. Note that the first suffix may vary according to other limitations; for example, for unsaturated alkyl groups, the first suffix must be at least 2; for cycloalkyl groups, the first suffix must be at least 3; etc.

Examples of saturated (unsubstituted) alkyl groups include, but are not limited to, methyl (C1-6), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), hexyl (C3), heptyl ( C7) -alkyl, C7-alkyl, C6-alkyl, C7-alkyl, C7-alkyl, C7-alkyl,

Examples of saturated linear (unsubstituted) alkyl groups include, but are not limited to, methyl (C 1), ethyl (C 2), n-propyl (C 3), n-butyl (C 4), n-pentyl (amyl) C5), n-hexyl (Ce) and n-heptyl (C7).

Examples of saturated (unsubstituted) branched alkyl groups include isopropyl (C3), iso-butyl (C4), sec-butyl (C4), tert-butyl (C4), iso-pentyl (C5) and neo-pentyl (C5)

Alkenyl: The term " alkenyl " as used herein refers to an alkyl group having one or more carbon-carbon double bonds. Examples of alkenyl groups include C 2-4 alkenyl, C 2-7 alkenyl, C 2-10 alkenyl,

Examples of unsaturated (unsubstituted) alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH = CH 2), 1-propenyl (-CH = CH- CH 3), 2-propenyl (allyl, -CH = CH2), isopropenyl (1-methylvinyl, -C (CH3) = CH2), butenyl (C4), pentenyl (C5) and hexenyl (C6).

Alkynyl: The term " alkynyl " as used herein refers to an alkyl group having one or more carbon-carbon triple bonds. Examples of groups of alkynyl groups include C2-4 alkynyl, C2-7 alkynyl, C2-2 alkynyl,

Examples of unsaturated (unsubstituted) alkynyl groups include, but are not limited to, ethynyl (ethynyl, -C = CH) and 2-propynyl (propargyl, -CH 2 -C = CH).

Cycloalkyl: The term " cycloalkyl " as used herein refers to an alkyl group which is also a cycloalkyl group; ie a monovalent unit obtained by removing a hydrogen atom from an alicyclic endocyclic atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated), a having from 3 to 20 carbon atoms (unless otherwise indicated), including from 3 to 20 ring atoms. Thus, the term " cycloalkyl " includes the cycloalkenyl and cycloalkynyl subclasses. Preferably, each ring has from 3 to 7 ring atoms. Examples of cycloalkyl groups include C3-20 cycloalkyl, C3-5 cycloalkyl, C3-7 cycloalkyl, C3-7 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (C6), cycloheptane (C7), methylcyclopropane (C4), dimethylcyclopropane (C5), methylcyclobutane (C5), dimethylcyclobutane (C6), methylcyclopentane (C6), dimethylcyclopentane (C7), methylcyclohexane (C7), dimethylcyclohexane · ≫ · Unsaturated monocyclic hydrocarbon compounds: cyclopropene (C3), cyclobutene (C4), cyclopentene (C5) cyclohexene (C6), methylcyclopropene (C4) dimethylcyclopropene (C5), methylcyclobutene (C5) dimethylcyclobutene (C6), methylcyclopentene (C6) dimethylcyclopentene (C7), methylcyclohexene (C7) dimethylcyclohexene (C8); Saturated polycyclic hydrocarbon compounds (C10), carano (C10), pinane (C10), borane (C10), norcarane (C7), norpinane (C7), norbornane (C7), adamantane (C10), decaline hydronaphthalene) (Cio); unsaturated polycyclic hydrocarbon compounds: camphene (Cio), limonene (Cio), pinene (Cio); polycyclic hydrocarbon compounds having an aromatic ring: indene (C9), indane (eg, 2,3-dihydro-1H-indene) (Cg), tetralin (1,2,3,4-tetrahydronaphthalene) , acenaphthene (C 12), fluorene (C 13), phenalene (C 13), acefenantrene (C 15), aceantrene (C 16), cholanthrene (C 20)

Heterocyclyl: The term " heterocyclyl " as used herein refers to a monovalent unit obtained by removing a hydrogen atom from an endocyclic atom of a heterocyclic compound, which unit has from 3 to 20 ring atoms (unless indicated to the contrary), of which from 1 to 10 are endocyclic heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.

In this context, the suffixes (e.g., C3_2o, C3_7, C5-6, etc.) denote the number of endocyclic atoms, or range of number of endocyclic atoms, either carbon atoms or heteroatoms. For example, the term " C 5-6 heterocyclyl " as used herein refers to a heterocyclyl group having 5 or 6 ring atoms. Examples of groups of heterocyclyl groups include C3-20 heterocyclyl, C5_2 heterocyclyl, C3_15 heterocyclyl, C5-15 heterocyclyl, C3-12 heterocyclyl, C5-12 heterocyclyl, C3-6 heterocyclyl, C5-10 heterocyclyl, C3-7 heterocyclyl, C5_7 heterocyclyl and C5_6 heterocyclyl.

Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from:

Ni: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (eg, 3-pyrroline, 2,5-dihydropyrrolo) (C5), 2H-pyrrole or 3 H -pyrrole isopyrrole, isoazole) (C5), piperidine (Οβ), dihydropyridine (Ce), tetrahydropyridine (Ce), azepine (C7);

Oi: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (Ce), dihydropyran (Ce), pyran (Ce), oxepine (C7); S1: thiirane (C3); thiolane (C4), thiolane (tetrahydrothiophene) (C5), thian (tetrahydrothiopyran) (C6), thynthane (C7); 02: dioxolane (C5), dioxane (C6) and dioxepan (C7); 03: trioxane (Ce); N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine (Ce);

NiO4: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (Ce), oxazine (Ce); 33

NiSi: thiazoline (C5), thiazolidine (C5), thiomorpholine (Ce); N 2 O 1: oxadiazine (Ce); O1S1: oxathioole (C5) and oxathane (thioxane) (Ce); and, N1O1S1: oxathiazine (Ce).

Examples of substituted (non-aromatic) monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, (C 5) furanoses, such as arabinofuranose, lyxhofuranose, ribofuranose and xylofuranose, and pyranoses (Ce), such as allopyranose, altropyranose , glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose and talopyranose.

Spiro-cycloalkyl or C3-7 heterocyclyl: The term " spiro-cycloalkyl or C 3-7 heterocyclyl " as used herein refers to a C 3-7 cycloalkyl or C 3-7 heterocyclyl ring attached to another ring by a single atom common to both rings.

ArylC5-2o: The term " C5-2 aryl " as used herein refers to a monovalent unit obtained by removing a hydrogen atom from an aromatic ring member of a C5-2 aromatic compound having said ring, or two or more rings (eg, fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring (s) is an aromatic ring. Preferably, each ring has from 5 to 7 ring atoms. 34

The endocyclic atoms may all be carbon atoms, as in " carboaryl groups " in which case the group may conveniently be referred to as a " C5-20 carboalkyl " ·

Examples of C 5-20 aryl groups which do not have endocyclic heteroatoms (ie C 5-20) carboaryl groups include, but are not limited to, benzene (ie, phenyl) (C 6), naphthalene (C 1 4), anthracene (C 14), phenanthrene (C 14) and pyrene (C 16 >

Alternatively, the endocyclic atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen and sulfur, as in " heteroaryl groups ". In this case, the group may conveniently be referred to as " C5_2heteroaryl " , wherein " C5_2 " denotes endociclic atoms, carbon atoms or heteroatoms. Preferably, each ring has from 5 to 7 endocyclic atoms, of which from 0 to 4 are endocyclic heteroatoms.

Examples of C 5-20 heteroaryl groups include, but are not limited to, C 5 heteroaryl groups derived from furan (oxole), thiophene (thiole), pyrrole (azolle), imidazole (1,3-diazole), pyrazole (1,2-diazole ), triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole and oxatriazole; and heteroaryl C6 groups derived from isoxazine, pyridine (azine), pyridazine (1,2-diazine), pyrimidine (1,3-diazine, e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) and triazine. The heteroaryl group may be attached via a carbon atom or a heteroatom ring. 35

Examples of C 5-20 heteroaryl groups which comprise fused rings include, but are not limited to, C 12 heteroaryl groups derived from benzofuran, isobenzofuran, benzothiophene, indole, isoindole; heteroarylCio groups derived from quinoline, isoquinoline, benzodiazine, pyridopyridine; C 9 heteroaryl groups derived from acridine and xanthene.

The groups defined above, e.g. alkyl, heterocyclyl, aryl, etc., alone or as part of another substituent, may be alone optionally substituted with one or more groups selected from the same and from the additional substituents listed below.

Halo: -F, -Cl, -Br and -I.

Hydroxy: -OH. Ether: -OR, in which R is an ether substituent, for example, a C 1-7 alkyl group (also referred to as a C 1-7 alkoxy group), a C 3-12 heterocyclyl group (also referred to as a C 3-12 heterocyclyloxy group) or a C 5-20 aryl group (also referred to as a C 3-7 aryl group) a C5-2 aryloxy group), preferably a C1-7 alkyl group.

Nitro: -NO 2.

Cyano (nitrile, carbonitrile): -CN.

Acyl (keto): -C (= O) R, where R is an acyl substituent, for example H, a C1-7 alkyl group (also referred to as C1-7 alkylacyl or C1-7 alkanoyl), a C3-20 heterocyclyl group such as C 3-20 heterocyclylacyl) or an aryl C 20-20 group (also referred to as C 5-10 arylacyl), preferably a C 1-7 alkyl group. Examples of acyl groups include, but are not limited to, -C (= O) CH 3 (acetyl), -C (= O) CH 2 CH 3 (propionyl), -C (= O) C (CH 3) 3 (butyryl) and -C (= O) Ph (benzoyl, phenone).

Carboxyl (carboxylic acid): -C00H. Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C (= O) OR, where R is an ester substituent, for example, a C1-7 alkyl group, a C3_20 heterocyclyl group or a C5-2 aryl group, preferably a C1-7 alkyl group. Examples of ester groups include, but are not limited to, -C (= O) OCH 3, -C (= O) OCH 2 CH 3, -C (= O) OC (CH 3) 3 and -C (= O) O Ph.

Amide (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C (= O) NR 1 R 2, wherein R 1 and R 2 are independently amino substituents as defined for amino groups. Examples of amido groups include, but are not limited to, -C (= O) NH 2, -C (= O) NHCH 3, -C (= O) N (CH 3) 2, -C (= O) NHCH 2 CH 3, and -C (= O) N (CH 2 CH 3) 2, as well as amido groups in which R 1 and R 2, together with the nitrogen atom to which they are attached, form a heterocyclic structure such as, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl and piperazinylcarbonyl.

Amino: -NR 1 R 2, wherein R 1 and R 2 are independently amino substituents, for example hydrogen, a C 1-7 alkyl group (also referred to as C 1-7 alkylamino or di-C 1-7 alkylamino), C 3-20 heterocyclyl group or a C5-7 aryl group, preferably H or a C1-7 alkyl group, or, in the case of a " cyclic amino group ", R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms. Examples of amino groups include, but are not limited to, -NH 2, -NHCH 3, -NHCH (CH 3) 2, -N (CH 3) 2, -N (CH 2 CH 3) 2 and -NHPh. Examples of cyclic amino groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, perhydrodiazepinyl, morpholino and thiomorpholino. The cyclic amino groups may be substituted on their ring with any of the substituents defined herein, for example, carboxyl, carboxylate and amido.

Acylamido (acylamino): -NR 1 C (= O) R 2, where R 1 is an amide substituent, for example hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group, preferably H or a C1-7 alkyl group, most preferably H, and R2 is an acyl substituent, for example a C1-7 alkyl group, a C3_20 heterocyclyl group or a C20 aryl group, preferably a C1-7 alkyl group. Examples of acylamide groups include, but are not limited to, -NHC (= O) CH 3, -NHC (= O) CH 2 CH 3 and -NHC (= O) Ph. R1 and R2 may together form a cyclic structure such as, for example, succinimidyl, maleimidyl and phthalimidyl:

succinimidyl maleimidyl phthalimidyl

Ureido: -N (R1) CONR2 R3 wherein R2 and R3 are independently amino substituents as defined for amino groups, and R1 is a ureido substituent, for example hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group preferably hydrogen or a C1-7 alkyl group. Examples of ureido groups include, but are not limited to, -NHCONH 2, -NHCONHMe, -NHCONH 2, -NHCONMe 2, -NHCON 2, -NMeCONH 2, -NMeCONH 2, -NMeCONH 2, -NMeCONMe 2, -NMeCONMe 2, and -NHC (= O) NHPh .

Acyloxy (reverse ester): -OC (= O) R, where R is an acyloxy substituent, for example a C1-7 alkyl group, a C3_20 heterocyclyl group or a C5-20 aryl group, preferably a C1-7 alkyl group. Examples of acyloxy groups include, but are not limited to, -OC (= O) CH 3 (acetoxy), -OC (= O) CH 2 CH 3, -OC (= O) C (CH 3) 3, Ph, -OC (= O) C6 H4 F and -OC (= O) CH2 Ph.

Thiol: -SH.

Thioether (sulphide): -SR, wherein R is a thioether substituent, for example, a C 1-7 alkyl group (also referred to as a C 1-7 alkylthio group), a C 3-10 heterocyclyl group or a C 5-20 aryl group, in a manner Preferred is a C1-7 alkyl group. Examples of C 1-7 -alkylthio groups include, but are not limited to, -SCH 3 and -SCH 2 CH 3.

Sulfido (sulfinyl): -S (= O) R, where R is a sulfoxide substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group preferably a C1- 7. Examples of sulfoxide groups include, but are not limited to, -S (= O) CH 3 and -S (= O) CH 2 CH 3.

Sulfonyl (sulfone): -S (= O) 2 R, wherein R is a sulfone substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group preferably a C1-7 alkyl group . Examples of sulfone groups include, but are not limited to, -S (= O) 20 (methanesulfonyl, mesyl), -S (= O) 2 CF3, -S (= O) 2 CH2 CH3 and 4-methylphenylsulfonyl (tosyl).

Thioamido (thiocarbamyl): -C (= S) NR 1 R 2, wherein R 1 and R 2 are independently amino substituents as defined for amino groups. Examples of amido groups include, but are not limited to, -C (= S) NH 2, -C (= S) NHCH 3, -C (= S) N (CH 3) 2 and -C (= S) NHCH 2 CH 3.

Sulfonamino: -NR1 S (= O) 2 R, wherein R1 is an amino substituent as defined for amino groups, and R3 is a sulfonamino substituent, for example, a C1-7 alkyl group, a C3_20 heterocyclyl group or a C5-20 aryl group, a preferred mode is a C1-7 alkyl group. Examples of sulfonamino groups include, but are not limited to, -NHS (= O) 2 CH 3, -NHS (= O) 2 Ph and -N (CH 3) S (= O) 2 C 6 H 5.

As mentioned above, the groups which form the substituent groups listed above, e.g. , C 1-7 alkyl, C 3-20 heterocyclyl and C 5-10 aryl, may themselves be substituted. Thus, the above definitions encompass substituent groups which are substituted.

Accordingly, a further aspect of the present invention provides a compound of formula I:

Wherein: X8 is N, and X5 and X6 are CH; R7 is a C2-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 aryloxy, C5-20 aryl, Amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-22 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino ),

R 3 and R 4 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C 1-7 alkyl , C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3_2 cycloalkenyl, C5-20 aryl, C5-20 aralkyl, ether, acyl, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3_2o heterocyclyl, C2-20 aryl, C2-20 heteroaryl, ether, acyl, Amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R2 is NRn5Rn6, a C2-20 heteroaryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3_20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl Acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C 2-7 alkenyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-12 heterocyclyl, C 5-12 aryl, C 5-10 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino) or a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, cycloalkenyl amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, C1-6 alkyl, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonyl, , cyano, carboxy, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkylC 3-7 cycloalkenyl, C 3-7 heterocyclylC 5-2o, C 5-10 heteroaryl, ether, acyl, ester, amido, amino, acylamido , ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), wherein

R 5 and R 16 are independently H, a C 1-7 alkyl group, a C 5-20 heteroaryl group, a C 5-20 aryl group or R 5 and R 6 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 endocyclic atoms wherein each C 1-7 alkyl, heteroaryl-C5-2cycloalkylC5-2 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-2cycloalkylC5-2 aryl Acyloxy, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano , carboxy, thiol, C 1-2 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-7 heterocyclyl, C 5-10 aryl, C 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureid thioamido and sulfonamino), or a pharmaceutically acceptable salt thereof, and wherein " C5-20 aryl " as used herein, refers to a monovalent unit obtained by removing a hydrogen atom from an aromatic endocyclic atom of a C5_20 aromatic compound < said compound having a ring, or two or more (eg, fused) rings, and having from 5 to 20 endocyclic atoms, and wherein at least one of said ring or rings is an aromatic ring and wherein the endocyclic atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen and sulfur; and with the proviso that when R2 is unsubstituted morpholino, R3 and R4 together with the nitrogen atom to which they are attached form an unsubstituted morpholino, R7 is not unsubstituted phenyl, and when R2 is unsubstituted piperidinyl, R3 is and R 4 together with the nitrogen atom to which they are attached form an unsubstituted piperidinyl, R 7 is not unsubstituted phenyl.

According to a further aspect of the present invention there is provided a compound of formula I (A):

wherein: one or two of X5, X6 and X8 is N, and the others are CH;

R 3 and R 4 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C 1-7 alkyl C 2-7 alkenyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-12 heterocyclyl, C 5-12 heteroaryl, C 5-12 heteroaryl, C 5-12 heteroaryl, carboxylic acid, acyl ester, amido, amino, acylamido, acyloxy, thioether, sulfoxide, sulfoxide, sulfonyl, thioamido and sulphonamino groups (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-22 heterocyclyl, C2-20 aryl, C2-20 heteroaryl, ether, acyl, ester , amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R 2 is selected from NR 5 R 6, a C 5-20 heteroaryl optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl , C3-20 heterocyclyl, C5_20 aryl, C5-20 aryl heteroaryl, acyl ester, amido amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy , thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C2-20 aryl, C20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide , sulfonyl, thioamido and sulfonamino), and a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl ^ 7, C3-7 cycloalkenyl, C3-2 cycloalkenyl, C5-2 aryl, C2-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy nitro, cyano, carboxy, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-7 cycloalkenyl, C 5-2 aryl, C 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioamido, sulfonyl, thioamido and sulfonamino), wherein R 5 and R 6 are independently H, a C 1-6 alkyl group, a C 5-20 heteroaryl group, a C 5-20 aryl group or R n 5 and R n 6 together with the nitrogen to which they are attached form a ring heterocyclic ring containing from 3 to 8 endocyclic atoms in which each C 1-7 alkyl, C 5-12 heteroaryl C 5-10 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carb heteroaryl, acyloxy, acyloxy, acyloxy, thioether, sulfoxide, sulfonyl, acyloxy, thioether, acyloxy, thioether, acyloxy, thioether, acyloxycarbonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-6 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 aryloxy, C5-2cn heteroaryl, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R03 is hydrogen or a C1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl , C3-20 heterocyclyl, C5-2cycloalkyl, C5-2cycloalkyl, C5-2cycloheteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro , cyano, carboxy, thiol, C1-7 alkyl, C2-7 alkenyl, C3-7 alkynyl, C3-7 cycloalkenyl, C3-7 cycloalkenyl, C3-20 cycloalkenyl, C5-2 aryl, C5-2 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide sulfonyl, thioamido and sulfonamino); and

R 1a is C (= O) R c 2, C (= S) R 3, SO 2 R 3, a C 5-20 heteroaryl optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-8 cycloalkenyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl amido, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups), a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, -7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkenyl, C3-7 cycloalkenyl, C2-20 aryl, C5_2 aryl, C5_2 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxyl, nitro, cyano, carboxyl, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-10 heterocyclyl, C 2-10 aryl, C 2-7 heteroaryl, acyl ester, amido, amino, acylamido, ureido, acyloxy , thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C1-10 alkyl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, 7, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 aryloxy, C5-2 aryl heteroaryl, C5-20 heteroaryl, ether, acyl ester, amido amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), wherein Rc2 and Rc3 are H, a C5-2 aryl group, a C5-2 heteroaryl group, a C1-7 alkyl group or NR1 R11 R11, wherein R11 is R12 are independently H, a C1-7 alkyl group, a C5-20 heteroaryl group, a C5-20 aryl group or R11 and R11 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms, wherein each C1-7 alkyl, C5-20 aryloxy or C5-20 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-6 cycloalkenyl, 7f heterocyclylC3-2c acylamino, acylamido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, , carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-2 aryl, C5-2 heteroaryl, ether, acyl, amido, amino, acylamido, ureido, acyloxy, thioether, S3 and sulfoxide, sulfonyl, thioamido and sulfonamino), and R is H, a C5-2 aryl group, a C5-2 heteroaryl group or a C1-6 alkyl group; wherein each C 1-7 alkyl, C 5-10 heteroaryl or C 5-20 aryl is optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-20 aryl heteroaryl, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol C 1-7 alkyl, C 2-7 aryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a pharmaceutically acceptable salt thereof, and wherein " C5-20 aryl " as used herein refers to a monovalent unit obtained by removing a hydrogen atom from aromatic ring atom of an aromatic C5_2cv compound having said compound a ring, or two or more rings (e.g. fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring (s) is an aromatic ring and wherein the ring atoms may include one or more heteroatoms, including but not limited to oxygen , nitrogen and sulfur. 49

Other Preferences

The following preferences may apply to each aspect of the present invention, where applicable. The preferences for each group can be combined with those for any or all other groups, as appropriate. X5, X5 and δδ X8 is N, and X5 and X6 are CH. R 7 R 7 is preferably selected from an optionally substituted C 20 -C 20 aryl group.

If R7 is a C2-C10 aryl group it is preferably a C5-C10 aryl and more preferably an C6-C6 aryl group. Most preferably R7 is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from halo, hydroxy, C1-7 alkyl and C1-6 alkoxy.

In one embodiment, R 7 is an optionally substituted C 1-10 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxy, and C 1-7 alkyl and C 1-6 alkoxy; (wherein the alkyl groups may be optionally substituted with one or more groups selected from halo, hydroxy, C1-7 alkoxy, amino and C5-6 aryl). In another embodiment, R 7 is an optionally substituted C 6-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxy, and C 1-6 alkyl; and C 1-7 alkoxy (wherein the alkyl groups may be optionally substituted with one or more groups selected from halo, hydroxy, C 1-7 alkoxy, amino and C 5-6 aryl). In another embodiment R 7 is a thiophenyl group or a phenyl group optionally substituted with one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl. In another embodiment R 7 is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or 3- -hydroxymethylphenyl. In yet another embodiment, R 7 is an aryl group. As defined in any of the examples 1a, 1b, 1d, 1a, 1a, 1a, 1a, 11a, 11a, 11a, 13b, lbd, lbe, lbf, lbg, lbh, lbi, lbj or lbr.

gN10 and n is preferably selected from C (= S) Rc3, an optionally substituted C5-2 heteroaryl group, an optionally substituted C5-20 aryl group and an optionally substituted C1-10 alkyl group wherein Rc3 is as previously defined.

If R 1 'is C (= S) R 3, then R 3 is preferably NR 11 R 11, wherein R 11 and R 12 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms. 51

If R11 is a C20-20 heteroaryl group it is preferably a C10-10 heteroaryl group and more preferably C5-6 heteroaryl group. Most preferably, it is an optionally substituted pyrazole group, wherein the optional substituents are preferably selected from halo, hydroxy, C1-7 alkyl and C1-7 alkoxy.

If R11 is a C5-20 aryl group, it is preferably a C5-10 aryl and more preferably C5-6 aryl group. Most preferably, it is an optionally substituted phenyl group, wherein the optional substituents are preferably selected from halo, hydroxy, C 1-7 -alkyl and C 1-7 -alkoxy.

If R 11 is a C 1-10 alkyl group, it is preferably a C 1-10 alkyl group and more preferably C 1-10 alkyl group. Most preferably it is an optionally substituted C 1-6 alkyl group, wherein the substituents are preferably selected from halo, hydroxy, C 1-7 -alkyl, ether, for example C 1-7 -alkoxy, thioether, for example C 1-7 -alkylthio, C 5-12 heterocyclyl, C 3-10 heteroaryl, cyano, ester, for example -C (= O) is C 1-7 alkyl, and amino, for example C 1-7 -alkylamino, di-C 1-7 -alkylamino and C 1-7 -alkoxycarbonylamino.

In one embodiment R11 is a group as shown in any of Examples 8a, 8b, 8c, 8c, 8c, 8c, 8c, 8c, 8c, 8c, 8c, 81c, 8n, 8c, 8c, 8c , 8aa, 8aa, 8aa, 8aa, 8aa, 8aa, 8aa, 8aa, 8aa, 8aa, 8aa, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a , 8ba, 8bb, 8bc, 8bd, 8be and 8bg. R03 is preferably an optionally substituted C1-6 alkyl group. More preferably R03 is an unsubstituted C1-3 alkyl group, preferably a C1-6 alkyl group. methyl. rNS and rN4

R 3 and R 4 together with the nitrogen to which they are attached preferably form a heterocyclic ring containing from 5 to 7 ring atoms, which may optionally be substituted. Preferred optionally substituted groups include, but are not limited to, morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) and pyrrolidinyl.

More preferably the group formed is morpholino or thiomorpholino, which is preferably unsubstituted. The most preferred group is morpholino. R2

In one embodiment R2 is selected from NRn5Rn6, an optionally substituted C5-2a heteroaryl group and an optionally substituted C5-2a aryl group.

In another embodiment R2 is selected from NRn5Rn6, an optionally substituted C5-6heteroaryl group and an optionally substituted arylC6 group. 53

In another embodiment R2 is phenyl optionally substituted with one or more groups selected from hydroxyl, amino, nitro, carboxyl, formyl, cyano, methyl, amido, methyl, methoxymethyl and hydroxymethyl.

In yet another embodiment R2 is an aryl group. As shown in any of Examples 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 91, 9m, 9n and 9ae.

Preferably R2 is NRn5 Rn6, wherein RN5 and RN6 are as previously defined, and more preferably RN5 and RN6 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms, which may be optionally substituted. Preferably, the ring has from 5 to 7 ring atoms. Preferred optionally substituted groups include, but are not limited to, morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) and pyrrolidinyl.

Preferred N-substituents for the piperazinyl and homopiperazinyl groups include esters, in particular esters which have a C 1-7 alkyl group as an ester substituent, e.g. -C (= O) OCH 3, -C (= O) OCH 2 CH 3 and -C (= O) O C (CH 3) 3.

Preferred C-substituents for the groups include C 1-4 alkyl, preferably methyl. The groups may have one or more substituents, for example one or two substituents.

More preferred groups are morpholino and piperidinyl. Preferably, these are substituted with one or two methyl substituents. If these groups have two methyl substituents, they are preferably on separate carbon atoms. Particularly preferred groups include:

In one embodiment of the invention there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R 7 is an optionally substituted aryl group;

R 3 and R 4 together with the nitrogen to which they are attached form a heterocyclic ring containing from 5 to 7 endocyclic atoms, which may optionally be substituted; and R2 is selected from NRn5Rn6, an optionally substituted heteroarylC5-2and heteroaryl, and an optionally substituted arylC5_2oaryl group.

In another embodiment, there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R7 is an optionally substituted C5-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxy, and C1-7 alkyl and C1-7 alkoxy (wherein the alkyl groups may be optionally substituted with one or more groups selected from halo, hydroxy, C1-7 alkoxy, amino and C5-6 aryl); R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted; and R2 is selected from NRn5Rn6, an optionally substituted C5-6heteroaryl group and an optionally substituted arylC6 group.

In another embodiment, there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R7 is an optionally substituted C5-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxy, and C1-7 alkyl and C1-7 alkoxy (wherein the alkyl groups may be optionally substituted with one or more groups selected from halo, hydroxy, C1-6 alkoxy -7, amino and C5-6 aryl);

R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or optionally substituted pyrrolidinyl; and R 2 is NR 5 R 6 wherein R 5 and R 16 together with the nitrogen to which they are attached form a heterocyclic ring containing from 5 to 7 ring atoms, which may optionally be substituted.

In another embodiment, there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R7 is an optionally substituted C5-6 aryl group, wherein the optional substituents are selected from cyano, halo, hydroxy, and C1-7 alkyl and C1-7 alkoxy (wherein the alkyl groups may be optionally substituted with one or more groups selected from halo hydroxy, C1-7 alkoxy, amino and C5-6 aryl);

R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted; and R 2 is NR 5 R 6 in which R 5 and R 6 together with the nitrogen to which they are attached form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl.

In another embodiment, there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R 7 is a thiophenyl group or a phenyl group optionally substituted with one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl; R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted; and R 2 is NR 5 R 6 in which R 5 and R 6 together with the nitrogen to which they are attached form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted.

In another embodiment, there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R 7 is a thiophenyl group or a phenyl group optionally substituted with one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl;

R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted; and R 2 is NR 5 R 6 in which R 5 and R 6 together with the nitrogen to which they are attached form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted on carbon by one or more C1-4 alkyl groups.

In another embodiment, there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R 7 is a thiophenyl group or a phenyl group optionally substituted with one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl; 59 rNS form,

and R 2 together with the preferably nitrogen to which a morpholino or thiomorpholino are attached; and R 2 is NR 5 R 6 in which R 5 and R 6 together with the nitrogen to which they are attached form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted on carbon by one or more C1-4 alkyl groups.

In another embodiment, there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R7 is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or 3-hydroxymethylphenyl group;

R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino or thiomorpholino; and R 2 is NR 5 R 6 in which R 5 and R 6 together with the nitrogen to which they are attached form a group 60

In another embodiment, there is provided a subset of compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R7 is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl or 3-hydroxymethylphenyl group;

R 3 and R 4 together with the nitrogen to which they are attached preferably form an unsubstituted morpholino; and R 2 is NR 5 R 6 wherein R 5 and R 6 together with the nitrogen to which they are attached form a

In one embodiment of the invention, there is provided a subset of compounds of formula I (A), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; Wherein R1 is selected from C (= S) Rc3, an optionally substituted C2-20 heteroaryl group, an optionally substituted aryl C20, and an optionally substituted C1-4 alkyl group wherein Rc3 is as previously defined; R03 is an optionally substituted C1-6 alkyl group; R 4 and R 4 together with the nitrogen to which they are attached form a heterocyclic ring containing from 5 to 7 ring atoms, which may optionally be substituted; and R2 is selected from NRn5Rn6, an optionally substituted C5_20 heteroaryl group and an optionally substituted arylC20-aryl group.

In another embodiment, there is provided a subset of compounds of formula I (A), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R11 is C (= S) R3, an optionally substituted C5-6 heteroaryl group, an optionally substituted C1-6 aryl group or an optionally substituted C1-6 alkyl group wherein R11 is NR11 R11 and wherein R11 is and R11 together with the nitrogen to which are attached form a heterocyclic ring containing from 3 to 8 ring atoms; R03 is an unsubstituted C1-3 alkyl group; 62

R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted; and R2 is selected from NRn5Rn6, an optionally substituted C5-6heteroaryl group and an optionally substituted arylC6 group.

In another embodiment, there is provided a subset of compounds of formula I (A), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R 10 is a C (= S) NR 11 R 11 group wherein R 11 and R 11 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms, or a pyrazole group optionally substituted with one or more groups selected from halo , hydroxy, C1-7 alkyl and C1-7 alkoxy or a phenyl group optionally substituted with one or more groups selected from halo, hydroxy, C1-7 alkyl and C1-7 alkoxy, or a C1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxy, C1-7 alkyl, ether, for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-2cylaryl, C3-2cycloheteroaryl, C5-2cycloalkyl, cyano, ester, for example -C (= O) OR wherein R is C1-7 alkyl, and amino, for example C 1-7 -alkylamino, di-C 1-7 -alkylamino and C 1-7 -alkoxycarbonylamino; R03 is a methyl group;

R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted; and R 2 is NR 5 R 6 wherein R 5 and R 6 together with the nitrogen to which they are attached form a heterocyclic ring containing from 5 to 7 ring atoms which may optionally be substituted.

In another embodiment, there is provided a subset of compounds of formula I (A), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH;

R11 is a C (= S) NR11 R11 group wherein R11 and R11 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms, or a pyrazole group optionally substituted with one or more groups selected from halo, hydroxy, C 1-7 alkyl and C 1-7 alkoxy or a phenyl group optionally substituted with one or more groups selected from halo, hydroxy, C 1-7 alkyl and C 1-7 alkoxy, or a C 1-6 alkyl optionally substituted with one or more groups selected from halo, hydroxy C 1-7 -alkyl, for example C 1-7 -alkoxy, thioether, for example C 1-7 -alkyl, C 20 -aryl, C 3-20 heterocyclyl, C 5-20 heteroaryl, cyano, ester, for example -C (= O) O R wherein R 1 is C 1-7 alkyl, and amino, for example C 1-7 -alkylamino, di-C 1-7 -alkylamino and C 1-7 -alkoxycarbonylamino; R03 is a methyl group;

R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted; and R 2 is NR 5 R 6 in which R 5 and R 6 together with the nitrogen to which they are attached form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted.

In another embodiment, there is provided a subset of compounds of formula I (A), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R11 and R11 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms, or a pyrazole group optionally substituted with one or more groups selected from halo, hydroxy, C1-7 alkyl and C1-7 alkoxy or a phenyl group optionally substituted with one or more groups selected from halo, hydroxy, C1-7 alkyl and C1-7 alkoxy, or a C1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxy, , for example C1-7 alkoxy, thioether, for example C1-7 alkylthio, C5-20 aryl, C3-20 heterocyclyl, C5-20 heteroaryl, cyano, ester, for example -C (= O) OR wherein R is C1-7 alkyl, and amino, for example C 1-7 -alkylamino, di-C 1-7 -alkylamino and C 1-7 -alkoxycarbonylamino; R03 is a methyl group;

R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted; and R2 is NRN5 Rn6 wherein R5 and R6 together with the nitrogen to which they are attached form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted.

In another embodiment, there is provided a subset of compounds of formula I (A), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; 66

R11 is a C (= S) NR11 R11 group wherein R11 and R11 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms, or a pyrazole group optionally substituted with one or more groups selected from halo, hydroxy, C 1-7 -alkyl and C 1-7 -alkoxy or a phenyl group optionally substituted with one or more groups selected from halo, hydroxy, C 1-7 -alkyl and C 1-7 -alkoxy, or a C 1-6 -alkyl optionally substituted with one or more groups selected from halo, hydroxy C 1-7 -alkyl, for example C 1-7 -alkoxy, thioether, for example C 1-7 -alkylthio, C 2-7 -aryloxy, C 3-20 -heteroaryl-, C 5-7 -cycloheteroaryl, ester, for example -C (= O) O R wherein R 1 is C 1-7 alkyl, and amino, for example C 1-7 -alkylamino, di-C 1-7 -alkylamino and C 1-7 -alkoxycarbonylamino; R03 is a methyl group; R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino or thiomorpholino group; and R 2 is NR 5 R 6 in which R 5 and R 6 together with the nitrogen to which they are attached form a morpholino, thiomorpholino, piperidinyl, piperazinyl (preferably N-substituted), homopiperazinyl (preferably N-substituted) or pyrrolidinyl optionally substituted on carbon by one or more C1-4 alkyl groups.

In another embodiment, there is provided a subset of compounds of formula I (A), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH;

R11 is a C (= S) NR11 R11 group wherein R11 and R11 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms, or a pyrazole group optionally substituted with one or more groups selected from halo, hydroxy, C1-7 alkyl and C1-7 alkoxy or a phenyl group optionally substituted with one or more groups selected from halo, hydroxy, C1-7 alkyl and C1-7 alkoxy, or a C1-6 alkyl group optionally substituted with one or more groups selected from halo for example C 1-7 -alkoxy, for example C 1-7 -alkyl, C 5-12 aryl, C 3-8 heterocyclyl, C 5-7 cycloheteroaryl, ester, for example -C (= O) O R wherein R is C 1-7 -alkyl and amino, for example C 1-7 -alkyl -7-amino, di-C1-7 alkylamino and C1-7 alkoxycarbonylamino; R03 is a methyl group; R 3 and R 4 together with the nitrogen to which they are attached preferably form a morpholino or thiomorpholino group; and R 2 is NR 5 R 6 wherein R 5 and R 6 together with the nitrogen to which they are attached form a

68

In another embodiment, there is provided a subset of compounds of formula I (A), and pharmaceutically acceptable salts thereof, wherein: X8 is N, and X5 and X6 are CH; R11 is a C (= S) NR11 R11 group wherein R11 and R11 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 endocyclic atoms, or a pyrazole group optionally substituted with one or more groups selected from halo, hydroxy, C1-7 alkyl and C1-7 alkoxy or a phenyl group optionally substituted with one or more groups selected from halo, hydroxy, C1-7 alkyl and C1-7 alkoxy, or a C1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxy C 1-7 alkoxy, thioether, for example C 1-7 alkylthio, C 5-10 aryl, C 3-10 heterocyclyl, C 5-10 heteroaryl, cyano, ester, for example -C (= O) O R wherein R 1 is C 1-7 alkyl and amino for example C 1-7 -alkylamino, di-C 1-7 -alkylamino and C 1-7 -alkoxycarbonylamino; R03 is a methyl group;

R 3 and R 4 together with the nitrogen to which they are attached preferably form an unsubstituted morpholino group; and R 2 is NR 5 R 6 in which R 5 and R 16 together with the nitrogen to which they are attached form a group 69

or

In another aspect of the invention, the particular compounds of the invention are any of the Examples or pharmaceutically acceptable salts thereof.

In a further aspect of the invention, the particular compounds of the invention are any of the Examples 1a, 1b, 1d, 1a, 1a, 2b, 11b, 11b, 11b, lbe, lbf, lbg, lbh, lbi, lbr, 8a, 00g and > 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, L1. > 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8ba, 8ba, 8bb, 8bc, 8bd, 8b, 8b, 9a, 9b, 9c 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9 and 9a, or the pharmaceutically acceptable salts thereof.

Isomers, Salts, Solvates, Protected Forms and Prodrugs

Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational or anomeric forms, including but not limited to cis- and trans- forms; forms E- and Z-; forms c-, t- and r-; endo- and exo- forms; R-, S- and meso forms; D- and L- forms; d- and I- forms; (+) and (-) forms; keto-, enol- and enolate forms; sin and anti forms; synclinal and anticlinal forms; a- and β- forms; axial and equatorial forms; boat shapes, chair, twisted, envelope and half chair; and combinations thereof, hereinafter collectively referred to as " isomers " (or " isomeric forms ").

If the compound is in crystalline form, it may exist in a number of different polymorphic forms.

It is to be noted that, except as discussed below for the tautomeric forms, "isomers" as used herein are structural (or constitutional) isomers (ie, isomers which differ in the bonds between atoms and not only by the position of atoms in space). For example, a reference to a methoxy group, -OCH 3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (eg, C1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec- and tert-butyl methoxyphenyl includes ortho-, meta- and para-methoxyphenyl). The above exclusion does not refer to tautomeric forms, for example keto, enol and enolate forms, for example, in the following tautomeric pairs: keto / enol, imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enetiol, N-nitroso / hydroxyace and nitro / acnitro.

Unless otherwise noted, a reference to a particular compound includes all such isomeric forms, including racemic (wholly or partially) and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic media) of such isomeric forms are known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.

Unless otherwise noted, a reference to a particular compound also includes the ionic forms, salts, solvates and protected forms thereof, for example, as discussed below, as well as the various polymorphic forms thereof.

It may be convenient or desirable to prepare, purify and / or handle a corresponding salt of the active compound, for example, a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are discussed in ref. 25.

For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO "), then a salt with a suitable cation may be prepared. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K +, alkaline earth cations such as Ca 2+ and Mg 2+, and other cations such as Al 3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R +, NH2R2 +, NHR3 +, NR4 +). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N (CH 3) 4+. 72

If the compound is cationic, or has a functional group which may be cationic (e.g., -NH2 may be -NH3 +), then a salt with a suitable anion may be prepared. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitroso, phosphoric and phosphorous. Examples of suitable organic anions include but are not limited to those derived from the following organic acids: acetic, propionic, succinic, glycolic, stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic, hydroxymaleic, phenylacetic , glutamic, aspartic, benzoic, cinnamic, pyruvic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, ethanedisulfonic, oxalic, isethionic, valeric and gluconic acids. Examples of suitable polymeric anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethylcellulose.

It may be convenient or desirable to prepare, purify and / or handle a corresponding solvate of the active compound. The term " solvate " is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, active compound salt) and solvent. If the solvent is water, the solvate may conveniently be referred to as a hydrate, for example, a monohydrate, a dihydrate, a trihydrate, and the like.

It may be convenient or desirable to prepare, purify and / or handle the active compound in a chemically protected form. The term " chemically protected form " as used herein refers to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, i.e., they are in the form of a protected or protective group (also known as a masked or masked group or a blocked or blocked group). When protecting a reactive functional group, reactions involving other unprotected reactive functional groups may be carried out without affecting the protected group; the protecting group can be removed, generally in a subsequent step, without substantially affecting the rest of the molecule. See, for example, ref. 26.

For example, a hydroxyl group may be protected as an ether (-OR) or an ester (-OC (= O) R), for example as: a t-butyl ether; a benzyl ether, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl); a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC (= O) CH 3, -OAc).

For example, an aldehyde or ketone group may be protected as an acetal or ketal, respectively, in which the carbonyl group (> C = O) is converted to a diether (> C (OR) 2) by reaction with, for primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide or a urethane, for example, as: a methylamide (-NHCO-CH 3); a benzyloxy-amide (-NHCO-OCH2 C6 H5, -NH-Cbz); as a t-butoxy-amide (-NHCO-OC (CH 3) 3, -NH-Boc); a 2-biphenyl-2-propoxy-amide (-NHCO-OC (CH 3) 2 C 6 H 4 C 6 H 5, -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH (-NH-Teoc), as a 2,2-trichloroethyloxy-amide (-NH-Troc), as an allyloxy-amide 74 (-NH-Alloc), as a 2-trimethylsilylethyloxy amide a 2-phenylsulfonyl) ethyloxy-amide (-NH-Psec); or, in suitable cases, as an N-oxide (> N0 ·).

For example, a carboxylic acid group may be protected as an ester, for example, as: a C1-7 alkyl ester (e.g., a methyl ester, a t-butyl ester); a C1-7 haloalkyl ester (e.g., a trihaloC1-7 alkyl ester); a tri-C 1-7 alkylsilyl-C 1-7 alkyl ester; or an arylC5_2oC1-7 alkyl ester (e.g., a benzyl ester, a nitrobenzyl ester); or as an amide, for example as a methylamide.

For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH 2 NHC (= O) CH 3).

It may be convenient or desirable to prepare, purify and / or handle the active compound in the form of a prodrug. The term " prodrug " as used herein refers to a compound which, when metabolized (e.g., in vivo), produces the desired active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration or metabolic properties.

For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable, metabolically unstable ester). During metabolism, the ester group (-C (= O) OR) is cleaved to produce the active drug. Such esters may be prepared by esterifying, for example, any of the carboxylic acid groups (-C (= O) OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection, if necessary. Examples of such metabolically unstable esters include those in which R is C 1-20 alkyl (e.g., -Me, -Et); aminoC1-7 alkyl (e.g., aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl); and acyloxyC1-7 alkyl (eg, acyloxymethyl, acyloxyethyl, eg, pivaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl, 1- (1-methoxy-1-methyl) ethylcarbonyloxyethyl, 1- (benzoyloxy) ethyl, isopropoxycarbonyloxymethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl, 1- (4-tetrahydropyranyloxy) carbonyloxyethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, (4-tetrahydropyranyl) carbonyloxymethyl and 1- (4-tetrahydropyranyl) carbonyloxyethyl).

Other suitable prodrug forms include the phosphonate and glycollate salts. In particular, hydroxyl groups (-OH) may be converted into phosphonate prodrugs by reaction with chlorodibenzylphosphite followed by hydrogenation to form a phosphonate group -0 P (= O) (OH) 2. Such a group can be eliminated by phosphotase enzymes during metabolism to produce the active drug with the hydroxyl group.

In addition, some prodrugs are enzymatically activated to produce the active compound, or a compound which, upon further chemical reaction, produces the active compound. For example, the prodrug may be a sugar derivative or other conjugated glycoside, or may be an amino acid ester derivative. 76

Acronyms

For convenience, many chemical units are represented using well known abbreviations, including but not limited to methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu) , phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy (MeO), ethoxy (EtO 2), ethoxy (nHex), cyclohexyl ), benzoyl (Bz) and acetyl (Ac).

For convenience, many chemical compounds are represented using well known abbreviations, including, but not limited to, methanol (MeOH), ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), ether or diethyl ether (Et 2 O ), acetic acid (AcOH), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF) and dimethylsulfoxide (DMSO). General Synthesis

The compounds of formula I may be represented by Formula 1:

wherein R 4 represents NR 3 R 4. 77

The compounds of Formula 1 may be synthesized from compounds of Formula 2:

When R7 is NR11 R11, i.e. by reaction with k7H. When R 7 is a C 3-10 heterocyclyl group or optionally substituted C 5-20 aryl group, i.e. by reaction with R 7 B (OAlk) 2, wherein each Alk is independently C 1-7 alkyl or together with the oxygen to which they are attached form a C 5-7 heterocyclyl group . When R is an amide, urea or sulfonamide group, i.e. by reaction with ammonia followed by reaction of the resulting primary amide with the appropriate acid chloride, isocyanate or sulfonyl chloride. When R7 is OR01 or SR11, i.e. by reaction with potassium carbonate in the appropriate alcohol or thiol solvent.

Accordingly, according to a further aspect of the present invention there is provided a process for the preparation of a compound of formula 1, from a compound of Formula 2:

wherein: R 4 is NR 3 R 4 wherein R 3 and R 4 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms; R2 is selected from H, halo, OR02, SRs2b, NRn5Rn6, an optionally substituted C5-2a heteroaryl group and an optionally substituted arylC20 group, wherein R2 and Rs2b are selected from H, an optionally substituted C5-20 aryl group, an optionally substituted C 5-10 heteroaryl group or an optionally substituted C 1-7 alkyl group, and R N 5 and R n 6 are independently selected from H, an optionally substituted C 1-7 alkyl group, an optionally substituted C 5-20 heteroaryl group and an optionally substituted C 5-10 aryl group, or R n 5 and R n 6 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms, comprising (a) when R7 is NR11 R11, reacting the compound of formula 2 with R7 H; or (b) when R 7 is a C 3-20 heterocyclyl group or optionally substituted C 5-20 aryl group, reaction of the compound of formula 2 with R 7 B (OAlk) 2, wherein each Alk is independently C 1-7 alkyl or together with the oxygen to which they are attached form a C 5-7 heterocyclyl group , or (c) when R 7 is an amide, urea or sulfonamide group, reaction of a compound of formula 2 with ammonia followed by reaction of the resulting primary amine with the appropriate acid chloride, isocyanate or sulfonyl chloride, or (d) when R 7 is OR 01 or SR 11, by reacting the compound of formula 1 in the presence of base in the appropriate alcohol or thiol solvent.

The compounds of formula I (A) may be synthesized by reacting a compound of Formula 1a:

wherein R 4 represents NR 3 R 4, and

R7 is

wherein Lv is a marda group, such as a halogen, for example chloro, or an OSO2 R group, wherein R is alkyl or aryl, such as methyl, by reaction with Rn10 NH2.

The compounds of Formula 1a may be synthesized by reacting a compound of Formula 1a, wherein R 4 represents NR 3 R 4, and R 7 is

OH

with an alkyl- or arylsulfonyl chloride in the presence of a base.

The compounds of Formula 1b may be synthesized by reacting a compound of Formula 2:

Formula 2 with R 7 B (OAlk) 2, wherein each Alk is independently C 1-7 alkyl or together with the oxygen to which they are attached form a C 5-7 heterocyclyl group.

The compounds of Formula 2 may be synthesized from compounds of Formula 3:

by reaction with HR4 (HNRn3Rn4) followed by reaction with HR2.

The compounds of Formula 3 may be synthesized from compounds of Formula 4:

Formula 4 for example by treatment with POCl 3 and N, N-diisopropylamine.

The compounds of Formula 4 may be synthesized from compounds of Formula 5:

Formula 5 for example by treatment with oxalyl chloride.

The compounds of Formula 5 may be synthesized from compounds of Formula 6, for example, by reaction with liquid ammonia followed by reaction with thionyl chloride and ammonia gas:

Cl or

OH Χ β Cl

Formula 6

Alternatively, the compounds of Formula 1 may be synthesized from compounds of Formula 2A:

Formula 2A

When R2 is NRn5Rn6, i.e. by reaction with R2H. When R 2 is a C 3-10 heterocyclyl group or optionally substituted C 5-20 aryl group, i.e. by reaction with R2B (OAlk) 2, wherein each Alk is independently C1-7 alkyl or together with the oxygen to which they are attached form a C5-7 heterocyclyl group . When R is OR02 or SRs2b, i.e. by reaction with potassium carbonate in the appropriate alcohol or thiol solvent.

Accordingly, according to a further aspect of the present invention there is provided a process for the preparation of a compound of formula 1 from a compound of formula 2A:

Formula 2A wherein R4 is NRn3Rn4 wherein R3 and R4 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms; and R 7 is selected from halo, OR 1, SR 1, NR 1 R 2, NRN 7 a C (= O) R c 1, NR N 7 b SO 2 R 2 a, an optionally substituted C 5-20 heteroaryl group or an optionally substituted C 5-10 aryl group wherein R 1 and R 2 are selected from H, Optionally substituted heteroaryl, optionally substituted heteroaryl, or optionally substituted C 1-7 alkyl; R 1 and R 12 are independently selected from H, an optionally substituted C 1-7 alkyl, an optionally substituted C 5-20 heteroaryl, an optionally substituted arylC 2 -20, and R 11 and R 11 together with the nitrogen to which they are attached form a heterocyclic ring containing between 3 and 8 endocyclic atoms; RC 1 is selected from H, an optionally substituted C 5-20 aryl group, an optionally substituted C 5-2 heteroaryl group, an optionally substituted C 1-7 alkyl group or NR 8 R 9, wherein R 8 and R 9 are independently selected from H, an optionally substituted C 1-7 alkyl group, a C 5-20 heteroaryl group an optionally substituted arylC2-20 aryl group or R8 and R9 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms; 84

R 2a is selected from H, an optionally substituted C 5-20 aryl, an optionally substituted C 5-20 heteroaryl or an optionally substituted C 1-7 alkyl group; and RN7a and RN7b are selected from H and a C1-4 alkyl group; (a) wherein R2 is NRn5 Rn6, reacting a compound of formula 2A with R2H, or (b) when R2 is a C3-20 heterocyclyl group or optionally substituted C5-20 aryl group, reacting a compound of formula 2A with R2B (OAlk) 2 in wherein each Alk is independently C 1-7 alkyl or together with the oxygen to which they are attached form a C 5-7 heterocyclyl group, or (c) when R is OR or SR, reacting a compound of formula 2A in the presence of a base in the alcohol solvent or thiol.

The compounds of Formula 2A may be synthesized from compounds of Formula 3:

by reaction with HR4 (HNRn3Rn4) followed by reaction with HR7 or HR7 equivalent. For example, when R 7 is a C 3-10 heterocyclyl group or optionally substituted C 5-20 aryl group, i.e. by reaction with R 7 B (OAlk) 2, wherein each Alk is independently C 1-7 alkyl or together with the oxygen to which they are attached form a C 5-7 heterocyclyl group ·

The present invention provides active compounds, specifically, active in inhibiting mTOR activity. The term " active " as used herein refers to compounds which are capable of inhibiting the activity of mTOR, and specifically includes compounds having intrinsic (drug) activity as well as prodrugs of such compounds, which prodrugs themselves exhibit little or no intrinsic activity.

One assay which can be conveniently used to evaluate the inhibition of mTOR provided by a particular compound is described in the examples below. The present invention further provides a method of inhibiting the activity of mTOR in a cell comprising contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition. Such a method may be practiced in vitro or in vivo.

For example, a sample of cells may be cultured in vitro and an active compound contacted with said cells, and the effect of the compound on those cells observed. As inhibition of the " effect " cell growth over a given time or the accumulation of cells in the G1 phase of the cell cycle over a given time. When it is found that the active compound exerts an influence on the cells, it can be used as a prognostic marker or diagnostic of the efficacy of the compound in methods of treating a patient with cells of the same cell type. The term " treatment ", as used herein in the context of treatment of a condition, generally refers to treatment and therapy of a human or an animal (eg, in veterinary applications), in which some desired therapeutic effect is achieved, for example, inhibition of progression of the condition, and includes a reduction in rate of progression, a stop at rate of progression, improvement of the condition, and cure of the condition. Treatment is also included as a prophylactic measure (i.e., prophylaxis). The term " auxiliary " as used herein refers to the use of active compounds together with known therapeutic means. Such media include cytotoxic drug regimes and / or ionizing radiation as used in the treatment of various types of cancer. Examples of auxiliary anticancer agents which could be combined with the compounds of the invention include, but are not limited to, the following: alkylating agents: nitrogen mustards, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil: Nitrosoureas: carmustine (BCNU), lomustine ( CCNU), semiminal (methyl-CCNU), ethyleneimine / methylmelamine, triethylenemelamine (TEM), triethylene thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine): alkylsulfonates; 87 bisulfan; Triazines, dacarbazine (DTIC): Antimetabolites; analogs of folic acid, methotrexate, trimetrexate, pyrimidine analogs, 5-fluorouracil, fluorodeoxyuridine, gemcitabine, cytosine arabinoside (AraC, cytarabine), 5-azacytidine, 2,2'-difluorodeoxycytidine: Purine analogs; β-mercaptopurine, β-thioguanine, azathioprine, 2'-deoxycoformicin (pentostatin, erythroxynonyladenine (NASH), fludarabine phosphate, 2-Chlorodeoxyadenosine (cladribine, 2-CdA): Topoisomerase I inhibitors: camptothecin, topotecan, irinotecan, Rubitimus: natural products, antimitotic drugs, paclitaxel, vinca alkaloids, vinblastine (VLB), vincristine, vinorelbine, Taxotere ™ (docetaxel), estramustine, estramustine phosphate, epipodophyllotoxins, etoposide, teniposide: Antibiotics, actimomycin D, daunomycin (rubidomycin) , IL-2, G-CSF, GM-2, G-CSF, G-CSF, G-CSF, G-CSF, CSF: Retinoic acid derivatives: Radiosensitizers, metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, ethanidazole, nimorazole, RSU 1069, E09, RB 6145, SR4233, nicotinamide, 5-bromodeoxyuridine, 5-iododeoxyuridine, bromodeoxycytidine: Platinum coordination complexes; cisplatin, carboplatin: Anthracenedione; mitoxantrone, substituted AQ4N urea, hydroxyurea; Methylhydrazine derivatives, N-methylhydrazine (MIH), procarbazine; Adrenocortical suppressor, mitotane (ο.ρ'-DDD), aminoglutethimide: Cytokines; interferon (α, β, γ), interleukin; Hormones and antagonists; adrenocorticosteroids / antagonists, prednisone and the like, dexamethasone, aminoglutethimide; Progestins, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate; Estrogens, diethylstilbestrol, ethinyl estradiol / equivalents; Antiestrogen, tamoxifen; Androgens, testosterone propionate, fluoxymesterone / equivalents; Antiandrogens, flutamide, gonadotrophin releasing hormone analogues, leuprolide; Non-steroidal antiandrogens, flutamide; EGFR Inhibitors, VEGF Inhibitors; Inhibitors of proteasome.

The active compounds may also be used as cell culture additives to inhibit mTOR, for example, to sensitize the cells to known treatments with chemotherapeutic agents or in vitro ionizing radiation.

The active compounds may also be used as part of an in vitro assay, for example, to determine if a candidate host is likely to benefit from treatment with the compound in question.

Cancer The present invention provides active compounds which are anticancer or auxiliary agents for the treatment of cancer. One of ordinary skill in the art is able to readily determine whether a candidate compound is or is not a carcinogenic state for any particular cell type, alone or in combination.

Examples of cancers include, but are not limited to, lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carcinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma, and leukemias.

Any type of cell, including but not limited to lung, gastrointestinal (including, eg, intestine, colon), breast (mammary), ovary, prostate, liver (hepatic), kidney (renal), bladder, pancreas , brain and skin. The anticancer treatment defined above may be applied as a single therapy or may involve, in addition to the compound of the invention, surgery or conventional radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of antitumor agents: - (i) other antiproliferative / antineoplastic drugs and their combinations, as used in clinical oncology, such as alkylating agents (eg cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (eg, anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example, vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotere and inhibitors of polyninase); and topoisomerase inhibitors (for example, epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (Ii) cytostatic agents such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfen), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists ( for example, goserelin, leuprorelin and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (for example, anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) anti-invasive agents (e.g., c-Src kinase family inhibitors such as 4- (6-chloro-2,3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl] ethoxy (2-chloro-6-methylphenyl) -2- {6- [4- (2-hydroxyethyl) piperazin-1-yl] (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and inhibitors of metalloproteinases such as marimastat, inhibitors the function of the urokinase plasminogen activator receptor or antibodies against Heparanase), (iv) inhibitors of growth factor function: for example, such inhibitors include antibodies against growth factor and antibodies to the growth factor receptor (e.g. For example, the anti-erbB2 antibody trastuzumab [Herceptin ™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any antibodies against growth factor or the growth factor receptor disclosed by Stern et al. Critique reviews on oncology / haematology, 2005, Vol. 54, ppll-29); such inhibitors also include tyrosine kinase inhibitors, for example epidermal growth factor family inhibitors (for example EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7- methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI 774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, factor family inhibitors hepatocyte growth inhibitors, platelet derived growth factor family inhibitors such as imatinib, serine / threonine kinase inhibitors (for example, Ras / Raf signaling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signaling through MEK and / or AKT kinases, inhibitors of the growth factor family hepatocyte inhibitors, c-kit inhibitors, abl kinase inhibitors, IGF receptor kinase inhibitors (insulin-like growth factor); (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and inhibitors of cyclin-dependent kinases, such as CDK2 and / or CDK4 inhibitors; (v) antiangiogenic agents such as those that inhibit the effects of vascular endothelial growth factor, [for example, the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin ™) and the receptor tyrosine kinase inhibitors VEGF, such as 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD6474, Example 2 in WO 92/32651), 4- 2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD2171, Example 240 in WO 00/47212), vatalanib (PTK787; WO 98/35985 ) and SU11248 (sunitinib, WO 01/60814), compounds such as those disclosed in International Patent Applications WO97 / 22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds acting by other mechanisms linomide, integrin function inhibitors avb3 and angiostatin)]; (vi) vascular deteriorating agents such as Combretastatin A4 and the compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213 ; (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras anti-dosage agent; (viii) gene therapy approaches, including for example approaches to replacing aberrant genes, such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene targeting enzyme prodrug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitro-reductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multidrug resistance gene therapy; and (ix) immunotherapy approaches, including, for example, ex vivo and in vivo approaches to increase the immunogenicity of tumor cells from the patient, such as transfection with cytokines such as interleukin 2, interleukin 4 or colony stimulating factor granulocyte macrophages, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies.

The active compound or the pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, systemically / peripherally or at the desired site of action, including but not limited to, oral (e.g., by ingestion); topical (including e.g., transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth or nose); rectal; vaginal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid and intrasternal; by implanting a deposit, for example, subcutaneously or intramuscularly. The individual may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (eg, a guinea pig, a hamster, a mouse, a mouse), murine (eg, a mouse), canine (eg, a dog) (eg, a monkey (eg, a gorilla, a chimpanzee, a chimpanzee, a chimpanzee, a chimpanzee, a monkey) orangutan, gibbon), or a human.

Formulation

Although the active compound may be administered alone, it is preferable to present it as a pharmaceutical composition (eg, formulation) comprising at least one active compound as defined above, together with one or more carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, pharmaceutically acceptable lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.

Thus, the present invention further provides pharmaceutical compositions as defined above, and methods of preparing a pharmaceutical composition comprising mixing at least one active compound, as defined above, together with one or more carriers, excipients, buffers, adjuvants, stabilizers or other pharmaceutically acceptable materials, as described herein. The term " pharmaceutically acceptable " as used herein refers to compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical advice, suitable for use in contact with the tissues of an individual ( eg, human) without toxicity, irritation, allergic response, or other problem or excessive complication, balanced with a reasonable benefit / risk ratio. Each vehicle, excipient, etc. must also be " acceptable " in the sense of being compatible with the other ingredients of the formulation.

Suitable carriers, diluents, excipients, etc. can be found in classic pharmaceutical texts. See, for example, ref. 27 to 29.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more auxiliary ingredients. In general, the formulations are prepared by uniformly and intimately binding the active compound with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

The formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, pellets, granules, powders, capsules, wafers, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, vapors , foams, lotions, oils, boluses, electuary or aerosols.

Formulations suitable for oral administration (e.g., by ingestion) may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granulate; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a folder. 96

A tablet may be prepared by conventional means, e.g. compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets may be prepared by pressing into a suitable machine the active compound in a loose form such as a powder or granulate, optionally mixed with one or more binders (e.g., povidone, gelatin, gum arabic, sorbitol, tragacanth, hydroxypropylmethylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycollate, crosslinked povidone, crosslinked sodium carboxymethylcellulose); surfactants or dispersing or wetting agents (e.g., sodium lauryl sulfate); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Molded tablets may be prepared by molding into a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally coated or scratched and may be formulated so as to provide slow or controlled release of the active compound employed therein, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile. The tablets may be optionally provided with an enteric coating, to provide delivery in portions of the intestine other than the stomach.

Formulations suitable for topical (e.g., transdermal, intranasal, ocular, buccal and sublingual) administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil. Alternatively, a formulation may comprise an adhesive or a dressing, such as a bandage or adhesive plaster impregnated with active compounds and optionally one or more excipients or diluents.

Formulations suitable for topical administration in the mouth include lozenges comprising the active compound in a flavored base, generally sucrose and gum arabic or tragacanth; pastilles comprising the active compound on an inert base, such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes comprising the active compound in a suitable liquid carrier.

Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.

Formulations suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example in the range of about 20 to about 500 microns, which is administered in a manner in which it is made a sniff, i. and. by rapid inhalation through the nasal passageway from a container of the powder held close to the nose. Suitable formulations wherein the carrier is a liquid for administration, for example as nasal spray, nasal drops or aerosol delivery from a nebulizer, include aqueous or oily solutions of the active compound.

Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurized pack with the use of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gases.

Formulations suitable for topical administration through the skin include ointments, creams and emulsions. When formulated in an ointment, the active compound may be optionally used with a paraffinic or water miscible ointment base. Alternatively, the active compounds may be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w / w of a polyhydric alcohol, an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. Topical formulations may desirably include a compound that improves the absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.

When formulated as a topical emulsion, the oil phase may optionally comprise only an emulsifier (also known as an emulsifier) or may comprise a mixture of at least one emulsifier with a fat or an oil or with a fat and an oil. Preferably, there is included a hydrophilic emulsifier together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include an oil and a fat. Together, the emulsifier (s) with or without stabilizer (s) constitute the so-called emulsifying wax, and the wax together with the oil and / or fat constitute the so-called emulsifying base for ointment, which constitutes the oily phase dispersed form of the cream formulations. 99

Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of the oils or fats suitable for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils susceptible to be used in the pharmaceutical emulsion formulations may be very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with adequate consistency to prevent leakage from the tubes or other containers. Mono- or dibasic straight chain or branched alkyl esters such as diisoadipate, isocetylstearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-palmitate -ethylhexyl or a mixture of branched chain esters known as Crodamol CAP, the latter three esters being preferred. These can be used alone or in combination depending on the properties required. Alternatively, high melting point lipids, such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for vaginal administration may be presented as pessaries, buffers, creams, gels, pastes, foams or sprays containing in addition to the active compound, those carriers which are known in the art to be suitable. 100

Formulations suitable for parenteral (eg, by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal) administration include aqueous and non-aqueous, isotonic, pyrogenic, sterile injectable solutions which may contain antioxidants, buffers, preservatives, stabilizers, bacteriostatic agents and solutes which render the formulation isotonic with the blood of the intended recipient; and sterile aqueous and non-aqueous suspensions, which may include suspending agents and thickeners, and liposomes or other microparticle systems which are designed to direct the compound to the components of the blood or to one or more organs. Examples of isotonic vehicles suitable for use in such formulations include Sodium Chloride Injection, Ringer's Solution or Lactated Ringer's Injection. Typically, the concentration of the active compound in the solution is from about 1 ng / ml to about 10 pg / ml, for example from about 10 ng / ml to about 1 pg / ml. The formulations may be presented in single dose or multidose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, just before of use. Extemporaneous injectable solutions and suspensions may be prepared from sterile powders, granules and tablets. The formulations may be in the form of liposomes or other microparticle systems which are designed to direct the active compound to components of the blood or to one or more organs. 101

Dosage

It will be understood that appropriate dosages of the active compounds, and compositions comprising the active compounds, may vary from patient to patient. Determination of the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or detrimental side effects of the treatments of the present invention. The level of dosage selected will depend upon a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds and or materials used in association, and to the age, gender, weight, condition, general health and prior medical history of the patient. The amount of the compound and route of administration will ultimately be at the discretion of the physician, although in general the dosage will be that necessary to achieve local concentrations at the site of action that achieve the desired effect without causing substantial harmful or deleterious side effects. In vivo administration may be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of the treatment. Methods for determining the most effective means and dosage of administration are well known to those skilled in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cells to be treated and the subject being treated. Single or multiple administrations may be performed at the dose level and standard to be selected by the attending physician. 102

In general, a suitable dose of the active compound is in the range of about 100 pg to about 250 mg per kilogram of body weight of the subject per day. When the active compound is a salt, an ester, a prodrug or the like, the amount administered is calculated on the basis of the parent compound and, therefore, the effective weight to be used is increased proportionally.

Examples General Experimental Methods Thin-layer chromatography was performed using Kieselgel 60 F254 plates on glass backing from Merck. The plates were visualized by the use of a UV lamp (254 nm). Silica gel 60 (particle sizes 40-63 pm) supplied by E.M. Merck was used for flash chromatography. RM NMR spectra were recorded at 300 MHz on a Bruker DPX-300 instrument. Chemical shifts were referenced relative to tetramethylsilane.

Purification and identification of library samples

Samples were purified on Gilson LC units. Mobile phase A - 0.1% aqueous TFA, mobile phase B - Acetonitrile; flow rate 6 mL / min; Gradient - typically started at 90% A / 10% B for 1 minute, rose to 97% After 15 minutes, was maintained for 2 minutes, then returned to the starting conditions. Column: Genesis 4 pm, column C18, 10 mm x 250 mm of 103

Jones Chromatography. Peak acquisition was based on UV detection at 254 nm.

Mass spectra were recorded on a Finnegan LCQ instrument in positive ion mode. Mobile phase A - 0.1% aqueous formic acid. Mobile phase B - Acetonitrile; Flow rate 2 mL / min; Gradient - started at 95% A / 5% B for 1 minute, rose to 98% B after 5 minutes and held for 3 minutes before returning to starting conditions. Column: Varies, but was always 50 mm x 4.6 mm C18 (currently Genesis C18 4 pm Jones Chromatography). Detection with Waters 996 PDA, scanning range 210-400 nm. Microwave synthesis

Reactions were performed using a Personal Chemistry ™ Emrys Optimiser microwave synthesis unit with a robotized arm. Power range between. 0-300 W at 2.45 GHz. Pressure range between 0-20 bar; temperature increase between 2-5 ° C / s; temperature range 60-250 ° C. Synthesis of 2,4,7-substituted pyridopyrimidine derivatives

OH

Cl

105

Intermediates: a) 2-Amino-6-chloronicotinic acid (Inter 2) To 2, β-dichloronicotinic acid (Inter 1) (1 equiv) was added liquid ammonia (sufficient to prepare a 0.6 M substrate solution in ammonia). The suspension was sealed in a pressure vessel which was then slowly warmed to 130øC. It was noted that at this temperature a pressure of 18 bar was observed. This temperature and pressure was maintained for an additional 16 hours, after which the mixture was cooled to room temperature. The pressure vessel was opened and the reaction poured into ice water (1 reaction volume). The resulting solution was acidified to pH 1-2 using concentrated HCl which caused the formation of a precipitate. The acidic mixture was allowed to warm to room temperature and was stirred in this manner for an additional 30 minutes. The suspension was then extracted with diethyl ether (3 x 400 mL). The combined organic extracts were then filtered and the filtrate concentrated in vacuo to give a white solid which was further dried over P 2 O 5 to give the title compound (90% yield and 96% pure) in a suitably pure form to be used without any m / z (LC-MS, ESP): 173 [M + H] + T / R = 3.63 min b) 2-Amino-6-chloronicotinamide (Inter 3) To a solution of 2- amino-6-chloronicotinic acid (Inter 2) (1 equiv) in anhydrous THF under an inert atmosphere was added thionyl chloride (3.3 equiv) dropwise. The reaction mixture was stirred at room temperature for 2 hours. After this time the reaction was concentrated in vacuo to give a crude yellow solid residue. The crude solid was dissolved in THF (equal to the initial reaction volume) and again concentrated in vacuo to give a yellow solid residue. The residue was once again dissolved in THF and concentrated as above to give a solid residue which was then dissolved in THF (to give a 0.3 M solution) and gaseous ammonia was bubbled through the solution for 1 hour. The resulting precipitate was removed by filtration and the filtrate concentrated in vacuo to give a yellow precipitate which was triturated with water at 50øC, then dried to give the title compound (92% yield, 93% purity), suitably m / z (LC-MS, ESP): 172 [M + H] + T / R = 3.19 min c) 7-Chloro-1H-pyrido [2,3- d ] Intermediate 4 To a stirred (0.06 M) solution of 2-amino-6-chloronicotinamide (Inter 3) (1 equiv) in anhydrous toluene under an atmosphere was added oxalyl chloride (1.2 equiv) in a dropwise manner. The resulting mixture was then heated to reflux (115øC) for 4 hours after which it was cooled and stirred for another 16 hours. The crude reaction mixture was then concentrated to half its volume in vacuo and filtered to give the desired product in a suitably pure form (95% yield, 96% purity) to be used without further purification. m / z (LC-MS, ESP): 196 [MH] T / R = 3.22 min 107 d) 2,4,7-Trichloro-pyrido [2,3- d] pyrimidine (Inter. suspension of the dione (Intermediate 4) (1 equiv) in anhydrous toluene under an inert atmosphere was slowly added diisopropylethylamine (3 equiv). The reaction mixture was then heated to 70øC for 30 minutes and then cooled to room temperature prior to the addition of POCl 3 (3 equivalents). The reaction was then warmed to 100 ° C for 2.5 hours, before being cooled and concentrated in vacuo to give a crude slurry which was then suspended in AcOEt and filtered through a thin pad of Celite ™. The filtrate was concentrated in vacuo to give a brown oil which was dissolved in CH 2 Cl 2 and stirred on silica gel for 30 minutes. After this time the silica was removed by filtration, the filtrate concentrated and the crude residue purified by flash chromatography (SiO2) to give the title compound in analytically pure form (48% yield, 96% purity). m / z (LC-MS, ESP): 234 [M + H] + T / R = 4.21 min e) 4-Amino- ) cooled (0-5 ° C) of the trichlorinated substrate (Inter. 5) (1 equiv.) in CH 2 Cl 2 was added diisopropylethylamine (1 equiv.) dropwise. The appropriate amine (1 equiv.) Was then added to the reaction mixture in portions over a period of 1 hour. The solution was kept at room temperature under stirring for an additional 1 hour, before the mixture was washed with water (2x1 reaction volume). The aqueous extracts were combined and extracted with CH 2 Cl 2 (2 x 1 reaction volume). The organic extracts were then combined, dried (sodium sulfate), filtered and concentrated in vacuo to give an oily residue which solidified upon prolonged drying. The solid was triturated with diethyl ether and then filtered and the cake washed with cold diethyl ether to leave the title compound in a suitably clean form to be used without any further purification.

Inter. 6a: 2,7-Dichloro-4-morpholin-4-yl-pyrido [2,3-d] pyrimidine; R4 = morpholino; (LCMS, ESP): 285 [M + H] + T / R = 3.90 min (92% yield, 90% purity) m / z

Inter. 6b: 2,7-Dichloro-4 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) -pyrido [2,3-d] pyrimidine; R4 = (2R, 6S) -2,6-Dimethyl-morpholino; (LC-MS, ESP): 313 [M + H] + T / R = 4.39 min f) 2,4-Diamino-7-chloropyridopyrimidines (Intermediate (1 equiv) followed by the appropriate amine (1 equiv) was added to a solution (0.2 M) of the appropriate dichloromethane substrate (Inter 6a or 6b) (1 equiv) in anhydrous dimethylacetamide under an inert atmosphere . The resulting mixture was heated for 48 hours at 70 ° C, before being cooled to room temperature. The reaction was diluted with CH 2 Cl 2 (1 reaction volume) and then washed with water (3x1 reaction volume). The organic extract was concentrated in vacuo to give a syrup which was dissolved in AcOEt (1 reaction volume) and washed with brine, before being dried (sodium sulfate) and concentrated in vacuo to give an oil . The crude residue was purified by flash chromatography (SiO 2, eluted with AcOEt: Hex (7: 3) to (1: 1)) to give the title compound as a yellow solid which was suitably cleaned to be used without any purification additional.

Inter. 7a: 7-Chloro-2 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) -4-morpholin-4-yl-pyrido [2,3-d] pyrimidine; R 4 = morpholine, R 2 = cis-dimethylmorpholine; (45% yield, 85% purity) m / z (LC-MS, ESP): 348 [M + H] + T / R = 4.16 min

Inter. 7b: 7-Chloro-4- (2-methyl-piperidin-1-yl) -2-morpholin-4-yl-pyrido [2,3-d] pyrimidine; R 4 = morpholine, R 2 = 2-methylpiperidine; (LC-MS, ESI): 348.1 [M + H] + T / R = 3.42 min (57% yield, 95% purity) m / z

Inter. 7c: 7-Chloro-4 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) -2 - ((S) -3-methyl-morpholin-4-yl) -d] pyrimidine (intermediate for compound 11k): R 4 = cis-dimethylmorpholine, R 2 = (S) -3-Methyl-morpholine; (48% yield, 90% purity) m / z (LC-MS, ESP): 378 [M + H] + T / R = 3.74 min

Inter. 7d) 7-Chloro-2 - ((S) -3-methyl-morpholin-4-yl) -4-morpholin-4-yl-pyrido [2,3- d] pyrimidine (Intermediate for compound 11a): R4 = morpholine, R 2 = (S) -3-Methylmorpholine; (LCMS, ESP): 350 [M + H] + T / R = 3.44 min (70% yield, 97% purity) m / z

Inter. 7e: 7-Chloro-2- (2-ethyl-piperidin-1-yl) -4-morpholin-4-yl-pyrido [2,3- d] pyrimidine (intermediate for compound 11a): R4 = morpholine, R2 = 2-Ethyl-piperidine; (M + H) + T / R = 3.78 min (110 g) 4-Amino-7-aryl-2-methyl- (1 equiv) in water (1 volume) was added to appropriate 2,7-dichloro-4-amino-pyridopyrimidine (1 equiv) (Inter 6a or 6b) potassium carbonate (2.5 equiv) and acetonitrile (1 volume). The mixture was degassed by bubbling nitrogen through the solution, while being sonicated for 15 minutes, prior to the addition of tetrakis (triphenylphosphine) palladium (0.03 equiv). The mixture was degassed for an additional 5 minutes, before being heated under an inert atmosphere at 95 ° C for 2 hours. After completion, the reaction was cooled to room temperature and filtered under vacuum. The filtrate was concentrated in vacuo to give a solid residue which was dissolved in CH 2 Cl 2 (1 volume) and washed with water (1 volume). The organic extract was then dried (MgSO4), filtered and concentrated in vacuo to give an amorphous solid which was triturated with Et2 O to leave the desired product as a fine powder.

Inter. 8a (R 4 = Morpholine, R 7 = 4-chlorophenyl) 2-Chloro-7- (4-chloro-phenyl) -4-morpholin-4-yl-pyrido [2,3-d] pyrimidine; 1 H NMR (300 MHz, CDCl 3) δ ppm 8.29-7.96 (m, 2H), 7.75 (d, J = 8.70 Hz, 1H), 7.54-7.21 (m, 2H), 5.29 (s, 1H), 3.91 (m, 8H).

The appropriate chlorinated substrate (Inter. 7a-e) (1 equiv.) Was dissolved in toluene / ethanol (1: 1) solution (0.02 M). Sodium carbonate (2 equiv.) And the appropriate boronic acid (1 equiv.) Were then added, followed by tetrakis (triphenylphosphine) palladium (0.1 equiv). The reaction vessel was sealed and the mixture exposed to microwave radiation (140øC, adjusted for medium absorption) for 30 minutes. After completion, the samples were filtered through a silica cartridge, washed with EtOAc and then concentrated in vacuo. The crude residue was then purified by preparative HPLC to give the compounds listed below. R7 R4 R2 Retention time (min) [m / z] Purity (%) OH OH NO * YY Vo 7, 66 466.6 89 lb jcr 0 1 * yy 9.56 440, 4 85 lc (Min) [m / z] (w / w) (w / w) (w / w) Purity (%) 1% Ti ..... Vo 4, 41 436.5 98 lf OH &lt;gt; The term &quot; N &quot; kA 4.13 452.3 99 Ig x? ΓΛ ΓΛ N N cf cf cf cf cf cf cf cf cf cf cf cf cf cf cf cf cf cf cf cf cf cf TV''! , or 4.66 390.1 96 1 / λ &lt; XX 4v 8.12 412.3 93 ij OH kc / - \, or wl-v_y: o 4,38 450,1 96 lk k <7 0 1 xx <v {* 7, 75 482,5 89 11 k 7, 88, 422, 499 .mu.m. Rx R4 R 2 Retention time (min) [m / z] Purity (%) ln - * o &gt; x = / N 0 ^ Vf- χτ <8.52 431.4 95 OH OH # 3 / OH OH 3.89 456.4 93 lp CH * XX vjv rr 4.36 480, 5.00 g of the compound of the formula: ## STR1 ## in which R 1 is hydrogen, 2 97 lt <X 0 ^ Vf- χτ -vj / v 4.66 426.3 98 lu-n-4, -0.467 420, 1 95 114 (continued) R7 R4 R2 Retention time (min ) [m / z] Purity (wt%) lv -bc / x-yyjrtr 4.53 426.3 99 lw - <xv F (/ Vf-XX -vj / v 9, 11 454, 4 100 lx - * cPh (/ Vf-XX Λ / λγ 8.93 445.3 97 iy (/ Vj-XX Λ ^ ν 4, 72 426, 499 lz <K (/ Vf- χχ / v | v 8.89 451.5 80 laa (/ Vj-χχ μ | λι 7.66 396.4 99 lab XX or HN- (Vf-XX a | v 7.65 463.4 85 lac); - XX μl λι 3.62 407, 4 99 115 (continued) R 7 R 4 R 2 Retention time (min) [m / z] Purity (% OH crcr xx 4.0.04 V4- 4.24 466.5 100 laf OH 0 4 V4- oX 6 4.33 484.496 lag 0 -4 V4- XX 4 4, 44 454.3 98 lah 0 ^ V4- XX 4 8.43 466.497 and 1 NH2. (1) (b) (b) (b) (b) (b) (c) (b) R7 R4 R2 Retention time (min) [m / z] Purity (%) Amino Acid / A / J / V 9.44 446.2 88 lam (/ Vf-Xr Λ / λ, 8.92 464, 490, and 9.85 456.4 97. The method of claim 1, wherein the compound of formula (I) 490, 475 lap "T" (/ Vf-xr A / J / V 4, 41 440.3 99 laq O1- (/ Vf- XT Α / λ, 8.4 448.5 97 lar JQ-f O (/ Vf-Xr 'vJa 7.66 456.4 99 the 6 ^ O (/ Vf- Ό &quot; (m / z) Purity (%) lat A / J / V 8, 46 491.5 99 117 (continued) R7 R4 R2 Retention time (min) 97 464, 499 lau Λ Q * Xr Λ / λ, 8.35 431.5 93 lav Ή (-(/ / λ / λ, 8.59 450.4 99 law & lt X-A, J-V, X-A, J-V, X-A, 7.63 457.5 99 laz &lt;gt; X &quot; 'A / J / V 6, 4 408, 499 lba Κϊ Λ Λ Λ Α Λ Λ Λ 9.08 478, 4 99 118 (m / z) purity (wt%) lbb OH σ o Ό A / J / V 3.95 452.3 95 lbc OH σ 0 f f - â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ9.01, xr λ / λ, 4, 9 512.4 100 lbg J C σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ σ (Min) [m / z] Purity (%) Comp Ref. Lbj (w / w) xr 1 c, c / ε-HM 5, 45 353.2 100 lbk O-rO c / V4-Xr Λ / λ / 5, 43 518.4 96 lbl (X-A-J / V 11.28 502.3 95 Comp. Ref. = Reference Compound (not considered as an Example) R7 R4 R2 Retention Time (min) [m / z] Purity (%) lbm c / V4-Xi A / J / V 4.13 480.4 97 lbn ( / V4-Xj 'A / J / V 4, 79 464, 470 lbo c /-/ λ / λ, 5.2 492, 4 93 120 (retention) R7 R4 R2 Retention time (min) [m / z] Purity (%) lbp OH / c / γ / Î ± Î ± β A / J / V 4.5 508.4 90 æl w / V 4 - XX Λ / λ, 4, 81 476, 4 100 lbr (/ V4-XX A / J / V 9.44 450.3 98 lbs j and v4 -v | a 'O 4.65 424.3 99 lbt o ^ 3 (/ \ lf-XX Λ / λ , 9.26 506.3 98 lbs Qq / i-l-IX) 4.78 438.4 99 lbs OTl (/ ^ Nf-X &quot; α / λ / 11, 43 526.3 99 lbw (/ V4-χχ A / J / V 11.54 548.3 98 lbx w / V4-XX Α / λ, 5.37 506.4 95 121

NMR (CDCl3) δ ppm 8.72 (s, 1H), 8.46 (d, J = 8, 70), 8.37 (d, 2.34 Hz, 1H) , 8.17 (dd, J = 8.60, 2.34 Hz, 1H), 8.02 (d, J = 8, 77 Hz, 1H), 7.14 (d, J = 8.68 Hz, 1H), 4.59 (s, 1H), 3.95-3.71 (m, 8H), 2.50 (m, 3H).

To a solution of the appropriate chlorinated substrate (Inter. 7a-e) (1 equiv.) In 1,4-dioxane (0.04 M) was added to a solution of the appropriate chlorinated substrate (Compound 2a-2bg) amine (1.2 equiv.), cesium carbonate (2 equiv.), Xantphos ™ and tris (dibenzylideneacetone) dipalladium (0). The reaction vessel was sealed and exposed to heating under the influence of microwave radiation (normal absorption adjustment, 150øC, 20 minutes). The crude reaction mixture was then purified by preparative HPLC to give the compounds listed below. R4 R2 R7 Purity% m / z [MH] + TR (min) 2a 0N 1 * &quot; &quot; '&quot; Vo to ... _H 95 421 4, 65 2b 0 N 1 * YY Vo αχΑ &quot; 96 513 4, 12 2c N N 1 »...... d Ih h 95 451 3.6 122 (continued) R4 R2 R7 Purity% m / z [MH] + TR (min) 2d 0 N 1 * YY Vo 1 98 373.1 7, 18 2e 0 N 1 * YT Vo \ Ν Η 83 389.2 3, 73 2f 0 N 1 * YT Vo 1 Η 100 472.2 3.49 2g 0 1 w YY Vo Me ° 2C'N ^ Y1 χχ- Η 96 479.5 8.81 2h 0 V * γγ Y ° Η 85 446.5 8.34 21 0 N 1 * ,, ο ζγ Η 91 405.5 9.41 2j ô N 1 * γγ Vo χκ- Η 99 435.5 4.61 2k 0 N 1 * γγ ..... Vo "Όγ Η 86 455.5 9.68 21 ô N 1 * γγ Y ° ° 2ΝνΝ / CI 96 514 , 5 9.38 2m 1 1 * γγ Vo cV: ih t 100 525.6 10.46 (continued) R4 R2 R7 Purity% m / z [MH] + TR (min) 2n 0 N 1 * YY Vo 96 463.6 10.62 2nd 0 N 1 * YY Vo H 92 472.5 9.44 2p 0 N 1 w γγ JL, s * NH 98 553.6 11, 83 2q 0 N 1 * YY V 3 ° x c. H 97 486.6 10.22 2r 0 N 1 * YY Vv H 100 412, 4 3.5 2s 0 N 1 w YY Vo HVCl / * - HCl 92 538.2 10.59 2t 0 N 1 * YY V0 kAN- * H 86 436.2 3.44 2u 0 N 1 * YY Vo F fXYn · H 81 459.4 4.26 2v ô N 1 * γγ YY * 88 399.6 7, 96 124 (continued) R4 R2 R7 Purity% m / ζ [ΜΗ] + TR (min) 2w 0 N 1 * YY Vo Η 90 442.6 5, 13 2x 0 N 1 * YY Vo ν- ^ ν · &quot; Η 94 426, 4 8.52 2y 0 N 1 * γγ * &gt; 95 515.6 8, 71 2z 0 N 1 ★ γγ νχ Η 92 445, 499 49 2aa ô N 1 γγ YV ΟΗ 98 471.5 9.04 2ab 0 N 1 * γγ Vo Et2N Χΐ »- Η 69 492.6 6.25 2ac 0 N 1 * γγ Vo νο2 73 502.5 9.48 2ad 0 N 1 w γγ s- (1 1 Η 97 524.2 9,68 2ae 0 N 1 * γγ χχ Η 96 525, 4 4, 79 125 (continued) R4 R2 R7 Purity% m / ζ [ΜΗ] + TR (min) 2af 0 N 1 * γγ Vo α- Η 98 427.5 4.55 2ag 0 N 1 * γγ C ^ n ^ 'Η 100 413.4 4.36 2 ah 0 N 1 * γγ Δ_, Ν Η 95 385.3 3.88 2ai 0 N 1 * γγ Η 89 399.5 8.13 2a j 0 N 1 * γγ V &quot; Y 94 399.5 8.18 2ak 0 N 1 w γγ Vo Η 91 378.4 7, 81 2al 0 N 1 * γγ Vo XV Η 99 441.6 9.95 95 2am 0 N 1 * γγ Vo Η 92 385.5 7, 46 2an 0 N 1 * γγ Vo MeO-C- Η 99 469.4 4,3 4 2 2 N N 1 * γγ Vo ν-ν - ^ Jk Η 98 427 , 5 3.91 126 (continuation) R 4 R 2 R 7 Purity% m / z [MH] + TR (min) 2ap 0 N 1 * γγ Vo CN H 83 512.2 4.97 2aq 0 N 1 * γγ 94 427, 1 94 2ar 0 N 1 * γγ Υ ° ίΧ η 99 436.1 3.9 2as 0 N 1 * γγ Υ ° ΗΐΥ * ρ. Χ C02Me 98 48 Γ γ Μ Μ Μ Μ Μ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ Τ N 1 * γγ Υ ° ιΥ ^ Ν 1L s * II Η WN 99 473.6 4, 12 2aw 0 N 1 * γγ Vo N ^ j | CrNV ΥΓ 99 500.6 4.17 2ax 0 N 1 * γγ Υ ° / vKAn '- * UH 82 489.5 4, 84 127 (continued) R4 R2 R7 Purity% m / ζ [ΜΗ] + TR (min) 2 ay 0 N 1 * γγ Vo CC γ ^ Ν Η 98 488.5 4.56 2az 0 N 1 * &quot; &quot; ' Vo OÇ. Η 100 422.5 3, 73 2ba 0 N 1 * 'Ή' · &quot; ' &lt; χ. Η 100 422.5 3.6 2bb 0 N 1 * γγ C1.- Ν Ν Η 99 423.5 3.94 2bc 0 N 1 * γγ | Ν N An An- Η 97 423.5 4, 11 2bd 0 N 1 * γγ χγ Η 100 436.5 4.00 2be ô N 1 * γγ XI, 99 436.5 4, 49 2bf ô N 1 * γγ Υ Υ Α Α Λ Λ Λ Λ Λ 95 544.6 5, 23 2bg 0 N 1 * γγ Υ ° ^ ^ Ν tV 99 436.5 3.94 128 (continued)

Reference compound 2b: 1 H-NMR (300 MHz, CDCl 3) δ ppm 8.50 (s, 1H), 8.05 (d, J = 9.32 Hz, 1H), 7.10 (d, J = = 9.37 Hz, 1H), 4.46 (d, J = 12.95 Hz, 1H), 3.82-3.50 (m, 11H), 3.31 (s, 1H), 2.70 2.43 (m, 4H), 1.17 (d, J = 6.30 Hz, 1H)

Reference Compound 3 R 7 = NH 2 (Reference Compound 3a-b)

To a solution of the appropriate chlorinated substrate (Inter. 7â-e) (1 equiv) in isopropanol (0.6 M) was added aqueous ammonia concentrate (5 volumes). The reaction vessel was sealed and heated under the influence of microwave radiation (high absorption setting, 150øC, 30 minutes). The reaction mixture was then cooled, diluted with water (3 volumes) and extracted with AcOEt (2 x 3 volumes). The combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give a crude residue which was further purified by flash chromatography (SiO2) (Eluent-EtOAc / MeOH (95: 5) to (9: 1) ) to afford the compounds below in analytically pure form. R f to R 7 Purity% m / z [MH] + TR (min) 3a H N 1 * YY Vo X * h 2n 95 345.2 3.86 3b H 1n, h 2n 91 329.4 7.33

Reference Compound 4 R7 = Urea (Reference Compound 4a-i)

Appropriate anhydrous THF vessel 1 hour. (1 equiv.) To the solution (0.02 M) of the amino substrate (eg, Reference Compound 3a or 3b) (1 equiv.) Was added the appropriate isocyanate (2 equiv.). The reaction was sealed and heated to 60 ° C for the crude reaction mixture was then purified preparative to give the compounds below. R4 R2 R7 Purity% m / z [MH] + TR (min) 4a 0 N 1 * YY O Η H 99 416.5 3.8 130

Reference Compound 5 To a solution (0.02 M) of the appropriate amine substrate (Reference Compound 3a or 3b) (1 equiv) in anhydrous CH 2 Cl 2 was added triethylamine (2 equivalents ) and the appropriate acid chloride (2 equivalents). The mixture was stirred at room temperature for 1 hour, after which the solvent was allowed to evaporate at atmospheric pressure and the crude residue purified by preparative HPLC to give the below compounds. R4 R2 R7 Purity% m / z [MH] + TR (min) 5a 0 N 1 &quot; O &quot; '' V3 95 402.2 4.49 5b 0 TI 1 ♦ YY tv-0 96 441.2 4, 16 5c 0 N 1 »OH 100 413.2 3.89 5d Ò N 1 O 1 - UH 98 495, 2 4,34 5e 0 TI 1 0 [Γ Γ ^ Γ Γ Γ Γ Γ 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 z [MH] + TR (min) 5 g C °) N 1 * YY <VY Ν'-NH NH 2 99 454.5 3.85

Reference Compound 6 To a solution (0.02 M) of the appropriate amine substrate (Reference Compound 3a OR 3b) (1 equiv) in anhydrous CH 2 Cl 2 was added triethylamine (2 equiv) and the sulfonyl chloride (2 equiv.). The mixture was stirred at room temperature for 1 hour after which the solvent was allowed to evaporate under atmospheric pressure and the crude mixture purified by preparative HPLC to give the desired product. R4 R2 R7 Purity% m / z [MH] + TR (min) 60 0 N 1 * YY Vo 0 0 ^ .11 / N H 85 423.5 3.87 132

To a solution of the appropriate chlorinated substrate (Inter 7a-e) (1 equiv.) In the appropriate alcohol solvent (0.16M) was added potassium carbonate (5 equiv.). The reaction vessel was sealed and heated under the influence of microwave radiation (160øC, high absorption adjustment, 30 minutes). The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the desired product. R 4 R 2 R 7 Purity% m / z [MH] + RT (min) 70 0 V ΎΎ V 3 100 402.2 4, 49

Example 8

To a 0.1 M solution of Example 1a (1 equiv) in CH 2 Cl 2 was added Et 3 N (1 equiv) followed by methanesulfonyl chloride (1.1 equiv), which was added dropwise. The reaction was stirred under an inert atmosphere for 90 minutes after which it was quenched with water (2x1 volume), the organic extract was separated and dried (MgSO4), filtered and concentrated in vacuo. The crude yellow gum was then diluted with diethyl ether and stirred vigorously. The resulting yellow precipitate was then collected by filtration to give the title compound (98%) in a suitably clean form to be used without further purification. 7- (3-Chloromethyl-4-methoxy-phenyl) -2 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) -4-morpholin- d] pyrimidine; (LC-MS, ESP): No ionization [M + H] + T / R = 3.98 min To a 0.03 M solution of 7- (3-Chloromethyl-4-methoxyphenyl) -2 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) -4-morpholin-4-yl-pyrido [2,3-d] ] pyrimidine (1 equiv) in dimethylformamide was added potassium carbonate (2.6 equiv) followed by triethylamine (1 equiv.) and finally to the appropriate amine (1.1 equiv.). The reaction mixture was then heated to 40 ° C for 16 hours after which it was purified by preparative HPLC to give the desired product. 134

Purity (%) Retention time (min) [m / z] 8a 0.8% N (%) 99 3.86 519.5 8b - 0.77 6.32 8c ^ N, H Γ'0 '! ΊΊ ΊΊ r Y Y Y Y 98 98 98 98 5 5 5 5 N Νι / Η ^ Xr ^ XX 98 5, 96 509.4 8e v, o ^ ΛΑρ, 87 7.56 599.5 8f 0 ^ NH, continuation)

Purity (%) Retention time (min) [m / z] 8g Î'N / V x 10JJ o 99 3.88 519.5 8h PH PH PH Τ Τ Τ Τ , 57 578.5 8, 99, 6.21, 549.6, 8, 9, 9, 9, 10, 10, 10, 12, 12, 12, , 8 533.5 81 v P? -OOA-A-99 3.95 521.5 136 (continued)

Purity (%) Retention time (min) [m / z] 8m Λ 0> pH> 0.01> iAA kA 99 4, 18 575.58, or ocK '99 7, 14 547.5 8p XI 9 AvN 4 A / N' · '' '' '' '' and 75 7, 75 561.5 8q A. -7-oxo-4-oxo-1,2,3,4,5,6,7,8,8,10,11,12,12,12,12a T NH A 93 6.36 507.6 137 (continued)

Purity (%) Retention time (min) [m / z] 8s t rU SQ YH, ΥγΑ úcr 100 100 6, 71 551.5 8t A 0 γΑΥ A ° 99 4, 11 549.5 8u Y 0 AY αΛν AAiYN '· &quot; YJ or 98 6, 73 521.5 8v 1 0% A Α A A% An ΑΑΛΛλ - YJ Υ 99 6.25 523.4 8w ογ ρ2 Υ Υ 99 4.1 561.5 8x 0 0 7ΥΥ ΥαΑν ^ ΑγΑ AAi * &quot; ' γΑΥ Α 99 4, 14 571.4 138 (continued)

Purity (%) Retention time (min) [m / z] 8y * αχ <? Γ Λ l l l l l l l l l l l l l Γ l Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ. χ 3 k k i i 99 99 99 99 3 99 99 3 99 0.9 9.5 99 3.55 569.3 139 (continued)

Purity (%) Retention time (min) [m / z] 8e Λ 0 Ju o 99 3.42 662.3 8af a 9 r-A Or 0 · 99 4, 01 619.4 8ag òc Λ3 ^ ΧΛλΟ &quot; 99 3.96 575.38. Amino-AAN or O 99 4, 12 573.58a. (O 7 1 ku f ipvS OR o 99 3,61 576,5 8a 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Purity (%) Retention time (min) [m / z] 8ak 0 and AJ or 99 4, 01 553.4 8al 0 Λ-1 n ΠΝ A H. 1 n- &quot; Vhf / l N γγΑΛ0 · 83 4, 18 531.4 8am Q 0 / 1 i 8an 0 &lt; fl! XU O-92 4, 10 575, 488 T 0 C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C (%) 3%

Purity (%) Retention time (min) [m / z] 8max. Λ0 '98 4, 10 629.5 8as 0 Q N x rvx 9u ΛΛο' 99 4.20 650.5 8at 99 o Οχόχ- XX Xo 99 4, 11 600.4 8au oc. N r ^ ^ U λ λ λ λ λ λ λ λ λ λ λ λ λ λ λ λ λ λ and 94 4.20 581.5 8aw 35% 99% (%) 9.33 623.4 8ax X0% xx% xx% x% x% yu O 99 4, 17 589.4 142 (continuation)

Purity (%) Retention time (min) [m / z] 8 ay ° YO 0 83 4.22 626.5 8az 0 0 οΑ frS Vo 96 4, 41 631.5 8ba α * α ,, d ΆΆ A ° 89 5, 14 647.5 8bb Au · 0 Αη ΑΑΑΑρ- 99 3.95 601.4 8bc? 0 A ΑΑΛΑ ^ · &quot; Aj a ° 99 4.27 583.4 8bd 0 A oh A / -c- JL AA Air V ^ n ^ A ^ A * vU O 99 997.48 583.4 8b J 0 rAH Ai i 0.99 613.5 143 (continued)

Purity (%) Retention time (min) [m / z] 8bf --a λΛ 74 10.36 627.66bb 0-AJ O 93 7, 13 599.2

Example 9 R2 = aryl; (1 equiv) in acetonitrile / water (1: 1 - 0.025 M ratio) was added the appropriate 2-chloropyridopyrimidine (1eq) (1 equiv) , potassium carbonate (3.5 equiv) and tetrakis (triphenylphosphine) palladium (0.05 equiv). The mixture was heated to 95 ° C under an inert atmosphere for 2 hours and then cooled to room temperature. The reaction was then filtered through a thin pad of silica, which was washed with a 1: 1 mixture of MeOH / CH 2 Cl 2 (1 volume), concentrated in vacuo and then purified by preparative HPLC to give the desired product (9a- 9a) 144

Purity (%) Retention time (min) [m / z] 9a OH OH (ppm): 7.17 488.3 9b 0 oh ργΑΝ OH% 86 10, 16 518.3 9c 0 95 10, 72 474.3 9d 0 99 4.58 443.4 9e ÇH fs ^ Cu ΛΛρ J &gt; 95 4.53 459.4 9f 0 OH / V ^ N OX ^ o ^ y 97 7,21 419,3 145 (continued)

Purity (%) Retention time (min) [m / z] 9g 0 * 1 83 4.35 457.3 9h 0 97 4, 42 473.5 911 0 o OH 97 4.001 445.3 9 ^ VN 91 4, 70 454.3 9k 0 79 7, 19 472.3 91 NH; 89 7.24 444.3 9m 0, o V 98 4, 45 433.2 146 (continued)

Purity (%) Retention time (min) [m / z] 9n 0 · NH3 99 3.54 458.3 9o 0 96 11.05 505.3 9p 0 FFF 98 7, 49 471.2 9q 0 / ΐ 92 4.63 489.3 9.0 0 T T T T T F F F F F 99 11.32 497.3 9s 0 ΑΛ,, ΑΛ ΑΛ ΑΛ ΑΛ ΑΛ ΑΛ Λ Λ Λ Λ Λ )

Purity (%) Retention time (min) [m / z] 9u 0 XS → XX-96 5.24 433.2 9v 0 (PvS 0 Xr ^ x ^ 99 7, 18 448.2 9w 0 83 6.25 431.2 9x 0 99 5, 18 393.2 9 and 0 vr Nl-1. 6,27 479, 4 148 (cont'd)

Purity (%) Retention time (min) [m / z] 9ab 0 rvS N 96 6.20 428.3 9ac 0 97 2, 11 446.2 9ad 0 O &quot; 95 6.51 461.2 9a 0 OH 87 7.28 459.3

Example 10 Enzyme Assay

For mTOR enzyme activity assays, the mTOR protein was isolated from the cytoplasmic extract of HeLa cells by immunoprecipitation and the activity determined essentially as described above using recombinant PHAS-1 as a substrate (ref.21). 149

The following compounds were tested in this assay: 1a, 1b, 1a, 1a, 1a, 1a, 1a, 1a-1a, 1a-1a, 1a, 1a, lp, σ \ -1 lr, ls, lu, lv,,,,,,,,,,,,, lam, lan, lao, lap, laq, lar, lat, lau, lav, law,. lax, lay, laz, lba, lbb, lbc, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 21,2m, 2n, 2o, 2p, 2q, 2r, 2s 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2a, 2aq, 2a, 2a, 2a, 2aa, 2aa, 2aa, 2aa, 2aa, 2aa, 2ba, 2bb, 2bc, 2bd, 2be, 2bf, 2bg, 8bm, 8bn, 4a, 5a, 5b, 5c, 5d, 5f, 5g, 6, 7, 8a, 8b, 8c, co to &gt; 8e, 8f, 8g, 8h, 8i, 8j, 8k, 8: 1, 8m, 8n, 80, 8p, 8q, 8r, 8s, 8t, 8u, 8v, 8w, 8x, r8y, 8z, 8a, 8ab 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, , 8bb, 8bc, 8bd, 8b, 8bf and 8bg.

All tested compounds exhibited IC50 values against mTOR of less than 10 Âμm. The following compounds exhibited IC50 values against mTOR of less than 1 μM: laa, lab, lac, lad, 1a, la, la, la, la, la, lam, lan, la, lap, laq, lar, las , lat, lau, lav, law, lax, lc l-1 lr, ls, lt, lu, lv, lw, lx, ly, lz, 2a, 2a, 2ac, 2ad, 2af 2 ah, 2ap, 2aq, 2ar 2b, 2b, 2b, 2b, 2e, 2b, 2h, 2i, 2j, 2k, 2n, 2p, 2c, 2c, 2b, 2b, 2b, 3a, 3b 5c, CO &gt; 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8b, 8b, 8b and 8b, with the following compounds. exhibit IC50 values against mTOR of less than 100 nM: L1, L1, L1, L1, L1, L1, L1, L1, L1, L1, L1 / L1, L1b, L1c, CO 8b, 8c, 8d, 8e, 8f, H O & OO tr &gt; OD CO LJ. &gt; 8k, 81.8m, 8n, CO 0 &gt; 8aa, 8aa, 8aa, 8aa, 8aa, 8aa, 8aq, 8aq, 8a, 8a, 8aa, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8b. 8bc, 8b, 8bg. For example, Compound

lk has an IC50 of 0.043 pM 150

Example 11

Alternative Enzyme Assay The assay utilized AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR.

A C-terminal truncation of mTOR spanning amino acid residues 1362 to 2549 of mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-labeled fusion in HEK293 cells as described by Vilella-Bach et al., Journal of Biochemistry, 1999, 274, 4266-4272. The HEK293 stable cell line with FLAG-labeled mTOR (1362-2549) was routinely maintained at 37øC with 5% CO 2 until a confluence of 70-90% in Dulbecco's modified Eagle's growth medium (DMEM; Invitrogen Limited , Paisley, UK, Catalog No. 41966-029) containing 10% heat-inactivated fetal calf serum (FCS, Sigma, Poole, Dorset, UK, Catalog No. F0392), 1% L-glutamine (Gibco, Catalog No. 25030-024) and 2 mg / ml Geneticin (G418 sulfate; Invitrogen Limited, UK, Catalog No. 10131-027). Upon expression in the mammalian cell line HEK293, the expressed protein was purified using the FLAG epitope tag using standard purification techniques.

Test compounds were prepared as 10 mM stock solutions in DMSO and diluted to water as needed to give a range of final assay concentrations. Aliquots (2 Âμl) of each compound dilution were placed in a well of Greiner (Greiner Bio-one) 384-well low volume white polystyrene (LV) plate. A mixture of 30 μl of purified recombinant mTOR 151 enzyme, biotinylated 1 μ pe peptide substrate (Biotin-Ahx-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val- Bachem UK Ltd), ATP (20 μΜ) and a buffer solution [comprising Tris-HCl buffer pH 7.4 (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5 mg / mL), DTT (1.25 mM) and manganese chloride (10 mM)] was stirred at room temperature for 90 minutes.

Control wells that produced a maximum signal corresponding to maximal enzyme activity were created using 5% DMSO instead of the test compound. Control wells that produced a minimum signal corresponding to the fully inhibited enzyme were created by adding EDTA (83 mM) instead of the test compound. These test solutions were incubated for 2 hours at room temperature.

Each reaction was stopped by adding 10 μl of a mixture of EDTA (50 mM), bovine serum albumin (BSA, 0.5 mg / ml) and Tris-HCl buffer pH 7.4 (50 mM) containing Monoclonal Antibody 1A5 against p70 S6-Kinase (T389) (Cell Signaling Technology, Catalog No. 9206B) and Streptavidin donor beads and Protein A acceptors AlphaScreen (200 ng; Perkin Elmer, Catalog No. 6760002B and 6760137R respectively) and the assay plates were left for about 20 hours at room temperature in the dark. The resulting signals arising from excitation with laser light at 680 nm were read using a Envision instrument from Packard. Phosphorylated biotinylated peptide is formed in situ as a consequence of mTOR-mediated phosphorylation. The phosphorylated biotinylated peptide which is associated with the Streptavidin AlphaScreen donor beads forms a complex with Antibody 152

Monoclonal 1A5 against p70 S6-Kinase (T3 89) which is associated with AlphaScreen Protein A acceptor beads. After excitation with laser light at 680 nm, the donor sphere: acceptor sphere yields a signal that can be measured. Therefore, the presence of mTOR kinase activity results in a test signal. In the presence of an mTOR kinase inhibitor, the signal strength is reduced. Inhibition of the mTOR enzyme for a given test compound was expressed as an IC 50 value. The following compounds were screened in this assay: Ibd, Ibb, Ibb, Ibm, Ibb, Ibp, Ibq, Ibb, Ibb, Ibb, Ibb, Ibw, Ibx, 2bf, 9a, 9b, 9d, 9e, 9f, 9g, -H σ ') <VO LJ. &gt; 9a, 9n, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9a, 9ab, 9a, 9a and 9a.

All tested compounds exhibited IC50 values against mTOR below 10pm. The following compounds exhibited IC50 values against mTOR of less than 1 Âμm: lbk, lbm, lbn, lb, lbp, lbq, lbb, lbs, lbt, lmb, 9m, 9n, 9p, 9r, 9aa and 9ad with the compounds following to show IC50 values against mTOR of less than 300 nM: lbd, lbe, 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9a, 91, 9j, 9k, 9i, 9h, lbg and lbf. For example, the

Compound 1b has an IC 50 of 0.057 pM

Example 12

Cell proliferation assay (GI50) Cell growth was assessed using the sulforhodamine B (SRB) assay (A). T47D cells (ECACC, 85102201) were routinely subcultured in RPMI (Invitrogen, 42401018) plus 10% fetal calf serum (FCS), 1% L-glutamine (Gibco BRL, 153 25030) to a confluency not greater than 80% . To perform the assay, T47D cells were applied at 2.5 x 10 células cells / well in 90 æl of RPMI plus 10% fetal calf serum, 1% L-glutamine in 96-well plates (Costar, 3904) and incubated at 37 ° C (+ 5% CO 2) in a humidified incubator. Once the cells completely adhered (typically after 4-5 hours of incubation), the plate was removed from the incubator and 10 μl of the diluent was added to the control wells (Al-12 and Bl-12). The compound was prepared at a six-point semi-logarithmic dilution at 10X the required final concentration e. for a range of 6 points from 30 μΜ to 100 nM in semi-logarithmic steps the dilution started at 300 μΜ on the motherboard. The dosage was terminated by the addition of 10 pL of compound at the highest concentration at Cl-12 to the lowest concentration at HI-12. The plates were then incubated for 120 hours prior to SRB analysis.

After completion of the incubation, the medium was removed and the cells fixed with 100 μl of 10% (w / v) ice-cold trichloroacetic acid. The plates were incubated at 4øC for 20 minutes and then washed four times with water. Each well of cells was then developed with 100 μl of 0.4% (w / v) SRB (Sulforhodamine B, Sigma, Poole, Dorset, UK, Catalog Number S-9012) in 1% acetic acid for 20 minutes, before washing four times with 1% acetic acid. The plates were then dried for 2 hours at room temperature. The dye from the developed cells was solubilized by the addition of 100 μl of 10 mM Tris Base to each well. The plates were shaken gently and left at room temperature for 30 minutes, before measuring the optical density at 564 nM in a Microquant microtiter plate reader. The concentration of inhibitor which elicits a 50% reduction in growth (G155) was determined by analyzing the intensity of development of the treated cells as a percentage of the vehicle control wells using the Excelfit software. (A) Skehan, P., Storung, R., Scudiero, R., Monks, A., McMahon, J., Vistica, D., Warren, JT, Bokesch, H., Kenny, S. and Boyd, MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 82, 1107-1112.

All tested compounds exhibited GI 50 values below ΙΟμΜ.

The following compounds exhibited GI 50 values below 1 μM, 8e, 8h, 8m, 8n, 80, 8p, 8q, 8s, 8v, 8w, 8x, 8y, 8z, 8aa, and 8ah, with the following compounds to be displayed GI 50 values below 300 nM: 1 g, 8a, 8b, co d &gt; M-100 CO &gt; 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8aa, 8aa, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8a, 8aa, 8aa, 8aa, 8aa, 8a, 8a, 8b, 8bb, 8bc, 8bd, 8b, 8b, 8bg. For example, Compound 1r has a GI 50 of 0.232 μΜ.

Example 13

Phospho-Ser473 Akt assay in vitro

This assay determines the ability of the test compounds to inhibit the phosphorylation of Serine 473 in Akt as assessed using Acumen Explorer technology (Acumen Bioscience Limited), a plaque reader that can be used to rapidly quantify image characteristics generated by scanning from laser.

A human breast adenocarcinoma cell line MDA-MB-468 (LGC Promochem, Teddington, Middlesex, UK, Catalog No. HTB-132) was routinely maintained at 37øC with 5% CO 2 until a confluence of 70- 90% in DMEM containing 10% thermally inactivated FCS and 1% L-glutamine.

For the assay, the cells were detached from the culture flask using &quot; Accutase &quot; (Innovative Cell Technologies Inc., San Diego, CA, USA; Catalog No. AT104) using standard tissue culture methods and resuspended in medium to give 1.7x105 cells per ml. Aliquots (90æl) were applied to each of the 60 internal wells of a Packard Black 96-well plate (PerkinElmer, Boston, MA, USA; Catalog No. 6005182) to give a density of -15,000 cells per well. Aliquots (90 μl) of culture medium were placed in the external wells to prevent edge effects. The cells were incubated overnight at 37 ° C with 5% CO 2 to allow them to adhere.

On day 2, the cells were treated with test compounds and incubated for 2 hours at 37øC with 5% CO 2. Test compounds were prepared as 10 mM stock solutions in DMSO and successively diluted as necessary with growth medium to give a range of concentrations that were 10 times the required final assay concentrations. Aliquots (10æl) of each compound dilution were placed in a well (in triplicate) to give the required final concentrations. As a minimal response control, each plate contained wells having a final concentration of 100 pM LY294002 156 (Calbiochem, Beeston, UK, Catalog No. 440202). As a maximal response control, the wells contained 1% DMSO instead of test compound. After incubation, the contents of the plates were fixed by treatment with a 1.6% aqueous solution of formaldehyde (Sigma, Poole, Dorset, UK, Catalog No. F1635) at room temperature for 1 hour.

All subsequent aspiration and lavage steps were performed using a Tecan 96-well plate washer (10 mm / s suction velocity). The fixative solution was removed and the contents of the plates were washed with phosphate buffered saline (PBS; 50æl; Gibco, Catalog No. 10010015). The contents of the plates were treated for 10 minutes at room temperature with an aliquot (50 μl) of a cell permeabilization buffer consisting of a mixture of PBS and 0.5% Tween-20. The permeabilization buffer was removed and the nonspecific binding sites were blocked by treatment for 1 hour at room temperature of an aliquot (50 Âμl) with a blocking buffer consisting of 5% skim milk powder [&quot; Marvel &quot;;(Trademark); Premier Beverages, Stafford, GB] in a mixture of PBS and 0.05% Tween-20. The &quot; blocking &quot; was removed and the cells were incubated for 1 hour at room temperature with rabbit anti-phospho-Akt (Ser473) antibody solution (50æl per well; Cell Signaling, Hitchin, Herts, UK, Catalog No. 9277) which had was diluted 1: 500 in &quot; blocking &quot; buffer. Cells were washed three times in a mixture of PBS and 0.05% Tween-20. Subsequently, the cells were incubated for 1 hour at room temperature with Alexafluor488-labeled goat anti-rabbit IgG (50 æL per well; Molecular Probes, Invitrogen Limited, Paisley, UK, Catalog No. A11008) which had been diluted to 1 : 500 in 157 blocking buffer. Cells were washed 3 times with a mixture of PBS and 0.05% Tween-20. An aliquot of PBS (50æl) was added to each well and the plates were sealed with black plate seals and the fluorescence signal was detected and analyzed.

Dose fluorescence response data obtained for each compound were analyzed and the degree of Serine 473 inhibition in Akt was expressed as an IC 50 value.

The following compounds were tested and exhibited a cellular IC50, measured by pAkt, of less than 25 μ: lbj, lbd, lbh, lbi, 9j, 9a, 9a, 9r, 9d, 9f, 9e, with the following compounds exhibiting an IC50 cell, as measured by pAkt, less than 2.5 μ: lbr, lbg, lbe, 91, 9n, 9k, 9h, 9g, 9m, and 9i. For example, compound 91 has an IC50 for pAkt of 2.2 uM

Reference List 1) Brown, et al., Nature, 369, 756-758 (1994) 2) Chiu, et al., Proc Natl Acad Sci, 91, 12574-12578 (1994) 3) Sabatini, et al. Cell, 78, 35-43, (1994) 4) Sabers, et al., J Biol Chem, 270, 825-822 (1995) 5) Abraham, Curr Opin Immunol, 8, 412-418 (1996) 6) Schmelze and Hall, Cell, 103, 253-262 (2000) 158

Proc Natl Acad Sci, 95, 1432-1437 7) d 8) d 9) 10 11 12 13 (2 14 15 16 17 18 (2 19 20

Burnett et al. 998)

Terada, et al., Proc Natl Acad Sci, 91,114,994) et al., EMBOJ, 16, 3693-3704 (1997) and Houghton, Nat Rev Cancer, 4, 335-348 et al., Genes Dev, 13, 1422 -1437 (1999) et al., Genes Dev, 15, 807-826 (2001) et al., Liver Transplantation, 7, 001) Woods and Marks, Ann Rev Med, 55, 169-178 (2004)) Dahia , Endocrine-Related Cancer, 7, 115-129 (200) Cristofano and Pandolfi, Cell, 100, 387-390 (2000)) Samuéis, et al., Science, 304, 554 (2004)) Huang and Houghton, Curr Opin Pharmacol, 3,003)) Sawyers, Cancer Cell, 4, 343-348 (2003) Huang and Houghton, Curr Opin in Invest Drugs, 3, 002) 7-11481

Jeffries,) Bjornsti) Gingras,) Neuhaus, (2004) 473-484) 371-377 295-304 159 21) Bringer, et al., EMBO J, 15, 5256-5267 (1996) et al., Cancer Res, 63, 8451-8460, (2003) 23) Lawrence, et al., Curr Top Microbiol Immunol, 279, 199-213 (2004) 24) Eshleman, et al., Cancer Res, 62, 7291-7297 (2002) 25) Berge, et al., J. Pharm. Sci., 66, 1-19 (1977). 26) Green, T. and Wuts, P., &quot; Protective Groups in Organic Synthesis &quot;, 3rd Edition, John Wiley and Sons (1999). 27) &quot; Handbook of Pharmaceutical Additives &quot;, 2nd Edition (ed M. Ash and I. Ash), 2001 (Synapse Information Resources,

Inc., Endicott, New York, USA). 28) &quot; Remington's Pharmaceutical Sciences &quot;, 20th edition, pub. Lippincott, Williams &amp; Wilkins, 2000. 29) &quot; Handbook of Pharmaceutical Excipients &quot;, 2nd edition, 1994.

Lisbon, November 26, 2012 160

Claims (13)

A compound of formula I: (Wherein: X8 is N, and X5 and X6 are CH; R7 is a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl C 2-7 alkenyl, C 3-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-20 aryl, C 20-20 aryl, ether, acyl, ester, amido, amino, acylamido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-10 heterocyclyl, C 5-20 aryl, C 5-10 heteroaryl, ether, acyl, ester, amido, amino , acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R 3 and R 4 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5- Amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-12 heterocyclyl, C 5-12 heteroaryl, C 5-20 heteroaryl, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R2 is selected from NRn5Rn6, a C5_20 heteroaryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-6 heterocyclyl, Acyloxy, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, C1-6 alkyl, nitro, cyano, carboxy, thiol, C 1-2 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-20 aryl, C 5-20 heteroaryl, ether, acyl ester, amido, amino, acylamido, ureido, acyloxy, thioamido and sulfonamino), and a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, cycle heteroaryl, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino groups (each optionally substituted with one or more substituents selected from the group consisting of C1-6 alkoxy, C1-6 alkoxycarbonyl, or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-2 cycloalkenylC5-2 aryl, C5-20 heteroaryl ether , acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfoxide, thioamido and sulfonamino), wherein R 5 and R 6 are independently selected from H, a C 1-7 alkyl group, a C 5-20 heteroaryl group and a C 5-20 aryl group or R 5 and R 6 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms wherein each C 1-7 alkyl, C 5-12 heteroaryl, C 5-10 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-10 heterocyclyl, C 5-10 aryl, C 5-20 heteroaryl, ether, acyl ester, amido, amino , acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-20 cycloalkyl, C3-7 cycloalkenyl, C3-7 cycloalkenyl ether, acylamido, ureido, sulfonyl, thioamido and C5-20 heteroaryl, C3-20 aralkyl, acyl, ester, amido, amino, acyloxy, thioether, sulfoxide, sulfonamino), or a pharmaceutically acceptable salt thereof, and wherein &quot; C5-20 aryl &quot; as used herein refers to a monovalent unit obtained by removing a hydrogen atom from an aromatic endocyclic atom of a C5-20 aromatic compound, or two or more rings (e.g. fused), and having from 5 to 20 endocyclic atoms, and wherein at least one of said ring or rings is an aromatic ring and wherein the endocyclic atoms may include one or more heteroatoms, including but not limited to oxygen , nitrogen and sulfur; &quot; alkyl &quot; as used herein refers to a monovalent unit obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise noted), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated); &Quot; alkenyl &quot; as used herein refers to an alkyl group having one or more carbon-carbon double bonds; &quot; alkynyl &quot; as used herein refers to an alkyl group having one or more carbon-carbon triple bonds; &quot; cycloalkyl &quot; as used herein refers to an alkyl group which is also a cycloalkyl group; i.e. a monovalent unit obtained by removing a hydrogen atom from an alicyclic ringocyclic atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated (eg partially unsaturated, fully unsaturated), which unit has from 3 to 20 carbon atoms (unless otherwise indicated), including from 3 to 20 ring atoms; &quot; ether &quot; as used herein refers to a group -OR, wherein R is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group; &quot; acyl &quot; as used herein refers to a -C (= O) R group, wherein R is H, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 20-20 aryl group; &quot; ester &quot; as used herein refers to a -C (= O) OR group, wherein R 1 is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group; &Quot; amido &quot; as used herein refers to a -C (= O) NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group , or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms; &quot; amino &quot; as used herein refers to a group -NR 2 R 2, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group or R 1 and R 2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring having from 4 to 8 carbon atoms; &quot; acylamido &quot; as used herein refers to a group -NR 1 C (= O) R 2, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group; R2 is a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C5-20 aryl group, or R1 and R2 may, together with the atoms to which they are attached, form a succinimidyl, maleimidyl and phthalimidyl group; &quot; ureido &quot; as used herein refers to a group -N (R1) CONR2 R3, wherein R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C2-20 aryl group or R2 and R3 taken together with the nitrogen atom to which they are attached form a heterocyclic ring having from 4 to 8 endocyclic atoms, and R 1 is hydrogen, a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-20 aryl group; &quot; acyloxy &quot; as used herein refers to a -OC (= O) R group, wherein R 1 is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group; &quot; thioether &quot; as used herein refers to a -SR group, wherein R 1 is a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-10 aryl group; &quot; sulphoxide &quot; as used herein refers to a group -S (= O) R, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-20 aryl group; &quot; sulfonyl &quot; as used herein refers to a group -S (= O) 2 R, wherein R 1 is a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group; &quot; thioamido &quot; as used herein refers to a group -C (= S) NR 1 R 2, wherein R 1 and R 2 are independently hydrogen, C 1-7 alkyl, C 3-10 heterocyclyl group or C 5-10 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms; &quot; sulfonamino &quot; as used herein refers to a group -NR 1 S (= O) 2 R, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group, and R 1 is a C 1-6 alkyl group, 7, a C 3-20 heterocyclyl group or a C 5-10 aryl group; and with the proviso that when R2 is unsubstituted morpholino, R3 and R4 together with the nitrogen atom to which they are attached form an unsubstituted morpholino, R7 is not unsubstituted phenyl, and when R2 is unsubstituted piperidinyl, R3 is and R 4 together with the nitrogen atom to which they are attached form an unsubstituted piperidinyl, R 7 is not unsubstituted phenyl. A compound according to claim 1, wherein R 1 is a phenyl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkenyl, C 3-7 heterocyclyl, C 5-20 aryl, C 5-20 aryl, C 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-10 heterocyclyl, C 5-10 aryl, C 5-20 heteroaryl, ether, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfoxide, thioamido and sulfonamino groups), and wherein the heteroatoms of any C2-20 heteroaryl or C3-220 heterocyclyl group are selected from nitrogen, oxygen and sulfur, and wherein &quot; arylC5-2 as used herein refers to a monovalent unit obtained by removing a hydrogen atom from an aromatic ring member of a C 5-20 aromatic compound, said compound having one ring, or two or more rings (e.g. fused), and having from 5 to 20 endocyclic atoms, and wherein at least one of said ring or rings is an aromatic ring and wherein the endocyclic atoms may include one or more heteroatoms, including but not limited to oxygen , nitrogen and sulfur; &quot; alkyl &quot; as used herein refers to a monovalent unit obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise noted), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated); &quot; alkenyl &quot; as used herein refers to an alkyl group having one or more carbon-carbon double bonds; &quot; alkynyl &quot; as used herein refers to an alkyl group having one or more carbon-carbon triple bonds; &quot; cycloalkyl &quot; as used herein refers to an alkyl group which is also a cycloalkyl group; ie a monovalent unit obtained by removing a hydrogen atom from an alicyclic ringocyclic atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated), which unit having from 3 to 20 carbon atoms (unless otherwise indicated), including from 3 to 20 ring atoms; &quot; ether &quot; as used herein refers to a group -OR, wherein R is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-10 aryl group; &quot; acyl &quot; as used herein refers to a group -C (= O) R, wherein R is H, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group; &quot; ester &quot; as used herein refers to a -C (= O) O group, wherein R 1 is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group; &quot; starch &quot; as used herein refers to a -C (= O) NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group or R 1 and R2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring having from 4 to 8 ring atoms; &quot; amino &quot; as used herein refers to a group -NR 2 R 2, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group, or R 1 and R 2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms; &quot; acylamido &quot; as used herein refers to a group -NR 1 C (= O) R 2, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-7 aryl group R 2 is a C 1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group or R1 and R2 may together with the atoms to which they are attached form a succinimidyl, maleimidyl and phthalimidyl group; &quot; ureido &quot; as used herein refers to a group -N (R1) CONR2 R3, wherein R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group or R2 and R 3, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms, and R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group; &quot; acyloxy &quot; as used herein refers to a -OC (= O) R group, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-20 aryl group; &quot; thioether &quot; as used herein refers to a -SR group, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 2-20 aryl group; &quot; sulphoxide &quot; as used herein refers to a group -S (= O) R, wherein R is a C 1-7 alkyl group, a C 3-10 heterocyclyl group, a C20-aryl group; &quot; sulfonyl &quot; as used herein refers to a group -S (= O) 2 R, wherein R 1 is a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-10 aryl group; &Quot; thioamido &quot; as used herein refers to a -C (= S) NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, C 1-7 alkyl group, C 3-10 heterocyclyl group or C 5-10 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms; and &quot; sulfonamino &quot; as used herein refers to a group -NR 1 S (= O) 2 R, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 20-20 aryl group, and R is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group A compound according to claim 2, wherein R 7 is a phenyl group optionally substituted with one or more groups selected from chloro, hydroxyl, methyl, methoxy, ethoxy, i-propoxy, benzyloxy and hydroxymethyl. A compound according to claim 2, wherein R 7 is a 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-hydroxymethyl-4-methoxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4- hydroxyphenyl, 3-hydroxyphenyl or a 3-hydroxymethylphenyl. A compound according to claim 1 wherein the compound is a compound of formula I (A): Wherein: X8 is N, and X5 and X6 are CH; R 3 and R 4 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C 1-7 alkyl, C 2-12 alkenyl C7-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C6-10 aryl, C5-210 heteroaryl, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, 7, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-12 heterocyclyl, C5_20 aryl, C5-20 heteroaryl, ether, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R 2 is selected from NR 5 R 6, a C 5-20 heteroaryl optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy and thiol, or C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl C7-20 aryl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected halo, hydroxyl, nitro, cyano, carboxyl, thiol, C 1-2 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-20 aryl heteroaryl C 20-20, ether, acyl ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), and a C5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, , C2-7 alkynyl, cy aryl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from the group consisting of C1-6 alkoxy, C1-6 alkoxycarbonyl, halo, hydroxyl, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-2 cycloalkenyl, C5-2 cycloalkenyl, C5-2 heteroaryl, ether, amido, amino , acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), wherein R N5 and R n6 are independently selected from H, a C1-7 alkyl group, a C5-20 heteroaryl group and a C5-20 aryl group or RN5 and RN6 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 ring atoms wherein each C 1-7 alkyl, C 5-10 heteroaryl, C 5-10 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 aralkyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-2 aryl, C5-2 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxyl, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-20 heterocyclyl, C 5-20 aryl, C 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); R03 is selected from hydrogen or a C1-6 alkyl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-6 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl C1 -C20 heterocyclyl, C5-20 aryl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano , carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); and R11 is selected from C (= O) Rc2, C (= S) Rc3, SO2 R3, a C5-20 heteroaryl optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C7-20 aryl, C5-20 aryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 aralkyl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), a C 5-20 aryl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C 1-7 alkyl, C2-7 alkynyl, C3-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-2cycloalkenylC5-2cn heteroarylC5-2o, ether, acyl, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a C 1-10 alkyl group optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkenyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl, C5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulphates (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 arylC3-20 aryl, C5_2heteroaryl, ether , acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfoxide, thioamido and sulfonamino) wherein Rc2 and Rc3 are selected from H, a C5-2 aryl group, a C5-20 heteroaryl group, 7 or NR11 R11, wherein R11 and R11 are independently selected from H, a C1-4 alkyl group, a C5-20 aryl group or a C5-20 aryl group or R11 and R11 together with the nitrogen to which they are attached form a heterocyclic ring containing between 3 and 8 ring atoms, wherein each C1-7 alkyl, C5-20 aryl heteroaryl or C5-20 aryl or heterocyclic ring is optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C3-7 cycloalkenyl, C3-7 cycloalkenyl, C3-20 cycloalkenyl, C5-2 aryl, C5-20 aryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-12 heterocyclyl, C5-2 aryl, C5-2 heteroaryl, ether , ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino); and R 3 is selected from H, a C 17-20 aryl group, a C 5-10 heteroaryl group or a C 1-7 alkyl group wherein each C 1-7 alkyl, C 5-10 heteroaryl or C 5-10 aryl is optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxy and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C2-20 aryl, C2-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, thiol, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, 20, C 5-20 heteroaryl, ether, acyl, ester, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido and sulfonamino), or a pharmaceutically acceptable salt thereof, and wherein &quot; C 5-20 aryl &quot;, as here i.e. refers to a monovalent unit obtained by removing a hydrogen atom from an aromatic ring atom of a C5-20f aromatic compound, said compound having one ring, or two or more rings (e.g. fused), and having from 5 to 20 ring atoms, and wherein at least one of said ring (s) is an aromatic ring and wherein the ring atoms may include one or more heteroatoms, including but not limited to oxygen , nitrogen and sulfur; &Quot; alkyl &quot; as used herein refers to a monovalent unit obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise noted), the which may be aliphatic or alicyclic, and which may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated); used refers to a group or more carbon-alkenyl double bonds, as here alkyl having one carbon; &quot; alkynyl &quot;, as alkyl having carbon; as used herein refers to a group of one or more carbon triple bonds &quot; cycloalkyl &quot;, as used herein, refers to an alkyl group which is also a cycloalkyl group; i.e., a monovalent unit obtained by removing a hydrogen atom from an alicyclic ringocyclic ring of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated), which unit has from 3 to 20 carbon atoms (unless otherwise indicated), including from 3 to 20 ring atoms; &quot; ether &quot; as used herein refers to a group -OR, wherein R is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group; &Quot; acyl &quot; as used herein refers to a group -C (= O) R, wherein R is H, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group; &quot; ester &quot; as used herein refers to a -C (= O) O group, wherein R is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group; &quot; amido &quot; as used herein refers to a -C (= O) NR 2 group, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-7 aryl or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms; &quot; amino &quot; as used herein refers to a group -NR 2 R 2, wherein R 1 and R 2 are independently hydrogen, a C 1-6 alkyl group, a C 3-20 heterocyclyl group or a C 5-10 aryl group, or R 1 and R 2 taken in together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms; &quot; acylamido &quot; as used herein refers to a group -NR 1 C (= O) R 2, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-12 aryl group R 2 is a C 1-7 alkyl group, a C 3-7 heterocyclyl group -2 or a C5-20 aryl group, or R1 and R2 may, together with the atoms to which they are attached, form a succinimidyl, maleimidyl and phthalimidyl group; &quot; ureido &quot; as used herein refers to a group -N (R1) CONR2 R3, wherein R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3_20 heterocyclyl group or a C5-20 aryl group, or R2 and R3, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms, and R1 is hydrogen, a C1-7 alkyl group, a C3_20 heterocyclyl group or a C5-20 aryl group; &quot; acyloxy &quot; as used herein refers to a -OC (= O) R group, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-20 aryl group; &quot; thioether &quot; as used herein refers to a -SR group, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-20 aryl group; &quot; sulphoxide &quot; as used herein refers to a group -S (= O) R, wherein R 1 is a C 1-7 alkyl group, a C 3-20 heterocyclyl group, or a C 5-20 arylsulfonyl group &quot; as used herein refers to a -S (= O) 2 R group, wherein R is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group; &quot; thioamido &quot; as used herein refers to a -C (= S) NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group, or R 1 and R 2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms; and &quot; sulfonamino &quot; as used herein refers to a group -NR 1 S (= O) 2 R, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-7 aryl group a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group A compound according to any one of claims 1 to 5, in which R 3 and R 4 together with the nitrogen to which they are attached form a morpholino group. A compound according to any one of claims 1 to 6, in which R 2 is NR 5 R 6, wherein R 5 and R 16 together with the nitrogen to which they are attached form a heterocyclic ring containing from 3 to 8 endocyclic atoms, which may be optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl and thiol, or C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-20 heterocyclyl, C5-20 aryl Amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide, sulfonyl, thioamido, and sulfonamino groups (each optionally substituted with one or more groups selected from halo, hydroxy, nitro, cyano, carboxyl, C 1-20 heteroaryl, , thiol, C1-7 alkoyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-2cycloalkylC5-20 aryl, C5-20 aryl, C5-20 heteroaryl, ether, amido, amino, acylamido, ureido, acyloxy, thioether, sulfoxide , sulfonyl, thioamido and sulfonamino), and wherein the endocyclic heteroatoms of the heteroaryl C 20-20 heterocyclic heteroaryl group or heterocyclic ring containing from 3 to 8 heteroaryl atoms are selected from nitrogen, oxygen and sulfur, and in which the aryl group as used herein refers to is a monovalent unit obtained by removing a hydrogen atom from an aromatic endocyclic atom of a C 5-20 aromatic compound, said compound having one ring, or two or more rings (e.g. fused), and having from 5 to 20 endocyclic atoms, and wherein at least one of said ring or rings is an aromatic ring and wherein the endocyclic atoms may include one or more heteroatoms, including but not limited to oxygen , nitrogen and sulfur; &quot; alkyl &quot; as used herein refers to a monovalent unit obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise noted), which may be aliphatic or alicyclic, and which may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated); used refers to a group or more carbon-alkenyl double bonds, as here alkyl having one carbon; &quot; alkynyl &quot; as used herein refers to an alkyl group having one or more carbon-carbon triple bonds; &quot; cycloalkyl &quot; as used herein refers to an alkyl group which is also a cycloalkyl group; i.e. a monovalent unit obtained by removing a hydrogen atom from an alicyclic endocyclic atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated), which unit having from 3 to 20 carbon atoms (unless otherwise indicated), including from 3 to 20 endocyclic atoms; &quot; ether &quot; as used herein refers to a group -OR, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 2-20 aryl group; &quot; acyl &quot; as used herein refers to a group -C (= O) R, wherein R is H, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 20-20 aryl group; &quot; ester &quot; as used herein refers to a -C (= O) O group, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 2-20 aryl group; &quot; starch &quot; as used herein refers to a -C (= O) NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-7 aryl group or R 1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms; &quot; amino &quot; as used herein refers to a group -NR 2 R 2, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group, or R 1 and R 2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms; &quot; acylamido &quot; as used herein refers to a group -NR 1 C (= O) R 2, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-7 aryl group R 2 is a C 1-7 alkyl group, C3-20 heterocyclyl group or a C5-20 aryl group or R1 and R2 may together with the atoms to which they are attached form a succinimidyl, maleimidyl and phthalimidyl group; &quot; ureido &quot; as used herein refers to a group -N (R1) CONR2 R3, wherein R2 and R3 are independently hydrogen, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group or R2 and R 3, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms, and R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group; &quot; acyloxy &quot; as used herein refers to a -OC (= O) R group, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 5-20 aryl group; &quot; thioether &quot; as used herein refers to a -SR group, wherein R 1 is a C 1-7 alkyl group, a C 3-12 heterocyclyl group or a C 2-20 aryl group; &quot; sulphoxide &quot; as used herein refers to a group -S (= O) R, wherein R is a C 1-7 alkyl group, a C 3-10 heterocyclyl group, a C20-aryl group; &quot; sulfonyl &quot; as used herein refers to a group -S (= O) 2 R, wherein R 1 is a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-10 aryl group; &Quot; thioamido &quot; as used herein refers to a -C (= S) NR 1 R 2 group, wherein R 1 and R 2 are independently hydrogen, a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-20 aryl group, or R1 and R2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 carbon atoms; and &quot; sulfonamino &quot; as used herein refers to a group -NR 1 S (= O) 2 R, wherein R 1 is hydrogen, a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 5-20 aryl group, and R is a C 1-7 alkyl group, a C 3-10 heterocyclyl group or a C 5-10 aryl group A compound according to claim 7, wherein R 2 is selected from morpholino, thiomorpholino, piperidinyl, piperazinyl, homopiperazinyl and pyrrolidinyl wherein each morpholino, thiomorpholino, piperidinyl, piperazinyl, homopiperazinyl and pyrrolidinyl may be optionally substituted on carbon with one or more more methyl groups. ~ 7. ' A compound according to claim 8, wherein R is or I. 11 A compound according to claim 1 selected from any of the following Examples: wherein R 1, R 2, R 3, R 4, Vo lx JX 0 N 1 * Vo lc (X 0 N 1 * YY X ° ld 0 N 1 * YY XO le 0 N 1 * Vo lf OH òcr (/ \ lj-lg jy or n-4-v_y ✓Oh (n-4-n-4-n-4-n-4-n-4-yl) Λ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ (n-4-yl) -N- (2-methoxyphenyl) -N-4- (2-methoxyphenyl) τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ τ (X, y), where x is the number of n-1, x, y, x, y, <0 ΓΛ ΓΛ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ χ ΓΛ ΓΛ ΓΛ ΓΛ IM IM IM IM IM IM IM. and / or lac ΓΛ, or n-4-βâ Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / | - 3 Wv lag (4) and (4) and (4) and (4) and (4) and (4) and (4). 0 ^ _ ^ N - $ - XX 4 lai ΓΛ < 0 Nf-xy 4 lam / "λ« 0 n-4 wv "σ 4 lan" 4 n-4 V V σ 4-lao ΛΆ, 0 Nf- v_ and XX v | / v (s), and (4) (4), where n is 0 to 4, and n is 0 to 4. Nf-W xr lat ΓΛ, 0 n-4 V σ lau o o n-4 V .. σ lav \ ΓΛ, 0 Nf- v_y Xr law <0 0 N-4 V σ <v | / v lax ΓΛ, 0 Khf- σ T lay &quot; 8 0 Nf -V_ / Xr laz 0 Nf-v_v σ &lt; - 4 lbb OH 0 N-4 - v_y xx 4 lbc OH 0 n-4 - v_ ^ α / | λ, XD lbd * Or 0 n-4 w XX 4 lbe 0 n-4 Ον lbf ¢ / \ - (b) . 0 n-4 wt 4 lbh n. XCH 0 4 n-4 χχ 4 lbi OH ΛΆ < (B) 4-hydroxy-4-hydroxy-4-methyl-4-oxo-4-oxo-4- 1, 2, 3, 4, 4, 5, 6, 8, 9, 10, 10, 4 lbq TCU / Λ, the N-F-W XX 4 lbr. X-4, X-4, X-4, and X-1, X-2, X-2, X-3, ; (X-1). ΓΛ < N-4- [4- (4-methoxyphenyl) -4-oxo-4- 35 (continued) 8d 0 &gt; N &gt; kh &lt; / RTI &gt; &lt; tb &gt; &lt; / RTI &gt; jfvS -Λ3 ti 8h ^ 3 Γ ° Ί \ Q VYV ^ Ay * '1 JU or 8i Ό' N ^ H fJJ or 8 8j, 0 \ n nj Nj nA ^ 0? NH A 36 (continuation) 8k o - 81 3! (- ', ·' Ά · O · 8m 0 ΤρΟ-ΑΛρ, - · N, - ^ Ν / ° 8n α J y yy ^ A ^ p ··· (A) (b) (b) (b) (c) (b) (b) (b) (b) xs S L L Já 8 8 8 8 8 8 8 8 ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ Ύ ..... ..... ..... ..... ..... ..... ..... ..... ........................ (ΧΛ) ΧΛ ΧΛ 8 f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f ΧΛ ΧΛ ΧΛ ΧΛ ΧΛ ((( 8af Λ 0, H i HX NU 0 Ò Ò Ò Ò Ò Ò Ò 8 8 8 8 8 8 8 8 X X X X X X X X X X X X X X X X X X X X X X X X X X X X 0 V ak ak ak ak Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ 41 (continued) 42 (continued) 8ba 0-χ. (1), (2), (2) and (2), and (2), and (2), we assume that Χ Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α Α. A. A v, XU gj 8be, _ 0 rηΧη λΛτ -JU Çi 8bf -α 0 ρΑκ V0 8bg 0 ^ γγ '' ^ 'pAn V-kJ,,' -JJ O 43 44 (continued) (Continued) 9o 0 9p 0 F 9q 0 9r 0 OH yy ^ -o F 9s 0 vXciu ^ Xk 9t 0 9u 0 Q 46 (continued) (continued) 9ac 0 ^ υΛΛ0Λ &gt; Or pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use as a medicament. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, without the conditions in the preparation of a medicament for the treatment of a disease enhanced by the inhibition of mTOR. Lisbon, November 26, 2012 48